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Nationwide study for KD patients currently in the hospital for treatment who need a second round of treatment.


UC San Diego KD Study

Evaluation of kd diagnostic test.

Study for KD patients that come through the Rady Children’s Hospital San-Diego ER to evaluate a diagnostic test for KD.

KD Genetic Study

Study on the genes of KD patients and their biologic parents to see how children are predisposed to developing the disease.

Adult KD Study

A collaboration with adult cardiologists to learn about the care and monitoring of adults who suffered from KD in childhood.

Atorvastatin Trial

A clinical trial to evaluate the treatment of children with acute Kawasaki disease and coronary artery disease with atorvastatin.

Seattle Children's KD Study

Aneurysm risk prediction.

A new study could improve the quality of life for children with KD at risk of developing coronary artery aneurysms.

medical research internship for kawasaki disease

Since my diagnosis 26 years ago, there have been many new KD discoveries, but the cause as well as a tried and true treatment has not been found. In order to make strides in KD research, participants are needed. I personally have volunteered for any Kawasaki Disease study that has been offered that I have been eligible as a way to help further research.
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  • Review Article
  • Published: 26 May 2020

Kawasaki disease: pathophysiology and insights from mouse models

  • Magali Noval Rivas   ORCID: orcid.org/0000-0001-5570-8928 1 , 2 &
  • Moshe Arditi   ORCID: orcid.org/0000-0001-9042-2909 1 , 2 , 3  

Nature Reviews Rheumatology volume  16 ,  pages 391–405 ( 2020 ) Cite this article

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  • Experimental models of disease
  • Immunopathogenesis
  • Inflammation
  • Vasculitis syndromes

Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.

Kawasaki disease is a childhood systemic vasculitis leading to the development of coronary artery aneurysms; it is the leading cause of acquired heart disease in children in developed countries.

The cause of Kawasaki disease is unknown, although it is suspected to be triggered by an unidentified infectious pathogen in genetically predisposed children.

Kawasaki disease might not be a normal immune response to an unusual environmental stimulus, but rather a genetically determined unusual and uncontrolled immune response to a common stimulus.

Although the aetiological agent in humans is unknown, mouse models of Kawasaki disease vasculitis demonstrate similar pathological features and have substantially accelerated discoveries in the field.

Genetic and transcriptomic analysis of blood samples from patients with Kawasaki disease and experimental evidence generated using mouse models have demonstrated the critical role of IL-1β in the pathogenesis of this disease and the therapeutic potential of targeting this pathway (currently under investigation in clinical trials).

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Kawasaki disease is a systemic vasculitis that affects infants and young children 1 , 2 , 3 . Kawasaki disease is now the leading cause of acquired heart disease among children in North America, Europe and Japan 4 , 5 . The cardiovascular sequelae resulting from childhood Kawasaki disease are increasingly recognized to extend into adulthood, and the disease is no longer considered self-limiting 6 , 7 , 8 , 9 . The triggering agents for Kawasaki disease remain unidentified; however, results from our laboratory 10 , 11 and others 12 , 13 are consistent with the interpretation that a conventional antigen is probably responsible. Coronary arteritis and predominantly coronary artery aneurysms (CAAs) occur in up to 30% of untreated children, although this rate is reduced to 5–7% in children treated with high-dose intravenous immunoglobulin (IVIG) 3 , 14 , 15 . IVIG treatment leads to CAA regression in 60–75% of patients with Kawasaki disease 16 , 17 . However, the exact mechanisms by which IVIG reduces the rate of cardiovascular complications are unknown 18 . Up to 15–20% of patients with Kawasaki disease do not respond to IVIG treatment, and these individuals have an increased rate of CAA development 3 , 15 , 19 , 20 , 21 .

Kawasaki disease is associated with infiltration of the coronary artery wall by a broad variety of innate and adaptive immune cells. Immunohistochemical analysis of human post-mortem tissues shows accumulation in the arterial wall of monocytes, macrophages and neutrophils 22 , 23 , and the presence of activated CD8 + T cells 24 as well as IgA + plasma cells 25 , 26 . The release of pro-inflammatory cytokines, such as TNF and IL-1β, by infiltrating immune cells promotes vascular endothelial cell damage and the development of CAAs 27 , 28 .

However, understanding of Kawasaki disease pathophysiology is limited by the low availability of human tissues of the disease, failure to identify specific aetiological agents triggering the disease, and incomplete understanding of the molecular and cellular mechanisms leading to cardiovascular sequelae. Therefore, experimental animal models mimicking the human features of Kawasaki disease and their translational utility have been invaluable to investigation of this disease. In this Review, we discuss advances from human and mouse studies that have contributed to an improved understanding of Kawasaki disease pathophysiology and the cellular and molecular circuitries involved in disease development. We also outline how evidence obtained from experimental mouse models of Kawasaki disease vasculitis has paved the way for the development of new efficient therapeutics to treat human Kawasaki disease.

Aetiological agents

The causative agents initiating the disease have still not been identified >50 years after the first description of Kawasaki disease. However, the trigger is suspected to be of viral origin and to enter the body through the mucosal surfaces in the lung 29 (Fig.  1 ). This hypothesis is supported by the seasonality of Kawasaki disease outbreaks, which is similar to that of other respiratory infections. In Japan, two seasonal peaks have been observed, one in winter and another in summer, whereas in the USA, the incidence peaks are observed during spring and winter 30 . Development of Kawasaki disease is age specific, with children from 6 months to 5 years of age at greatest risk 3 , 30 , 31 , which suggests a protective maternal passive immunity against the causative agent from birth to 6 months of age and the importance of immune system maturation in children ≥6 years of age 29 .

figure 1

Different aetiological agents, from viruses to environmental toxins, have been proposed as triggering agents for Kawasaki disease; however, none has been corroborated, and the aetiological agent remains unidentified. Increased numbers of IgA + plasma cells have been detected in the pancreas, the kidneys, the coronary artery wall and the respiratory tract of patients with Kawasaki disease. Patients with Kawasaki disease have increased concentrations of secretory IgA in their serum, indicative of defective intestinal barrier function and increased intestinal permeability. Changes in the gut microbiota composition (dysbiosis) have also been suggested to have a role in the development of Kawasaki disease. Single nucleotide polymorphisms in the genes listed have been associated with susceptibility to Kawasaki disease and disease severity. The current understanding is that Kawasaki disease is triggered in genetically predisposed children by a ubiquitous environmental stimulus that typically would not result in an uncontrolled immune response and development of vasculitis.

The clinical features of Kawasaki disease, such as high fever, skin rash and peeling, conjunctivitis and intense release of pro-inflammatory cytokines, are reminiscent of other infectious diseases such as staphylococcal and streptococcal toxic shock syndromes 32 . Some studies have shown that, compared with healthy control individuals, patients with Kawasaki disease have a skewed Vβ T cell repertoire and increased frequencies of circulating Vβ2 + and Vβ8.1 + T cells, leading to the early suggestion that a superantigen toxin might have a role in triggering Kawasaki disease 33 , 34 , 35 . However, similar results were not reproduced in later studies 36 , 37 , leading to the more generalized hypothesis that the development of Kawasaki disease might be triggered by multiple conventional antigens.

Several early studies showed reduced prevalence of antibodies to the Epstein–Barr virus (EBV) capsid antigen in Japanese children with Kawasaki disease compared with age and sex-matched control patients 38 , 39 , 40 , suggesting the involvement of an abnormal immune response to EBV in disease development. However, this difference in EBV antibody seropositivity could not be reproduced in other studies 41 , 42 , 43 . A human coronavirus was detected more frequently in respiratory secretions of patients with Kawasaki disease than in control individuals 44 , although, again, other studies could not replicate this finding 45 , 46 , indicating that the original association might have been coincidental. The possibility that a retrovirus is the triggering agent for Kawasaki disease has also been proposed, owing to detection of retrovirus-specific reverse transcriptase activity in the co-culture supernatant of peripheral blood mononuclear cells (PBMCs) from patients with Kawasaki disease but not controls 47 , 48 . However, this result could not be replicated in later studies 49 , 50 , 51 . A peptide recognized by antibodies produced during the acute phase of Kawasaki disease has been identified in 2020 (ref. 52 ). Although the protein epitopes seem similar to hepaciviruses 53 , further studies are required to determine the specific gene sequence from which this peptide emerges.

Altogether, the absence of consistent and reproducible studies pinpointing a specific aetiological agent suggests that Kawasaki disease is caused not by one but by multiple infectious agents. Acute Kawasaki disease is associated with infiltration of IgA + plasma cells in the respiratory tract, implying that the upper airways act as a portal of entry 25 , 26 . One suggestion is that the triggering agent might be an environmental toxin or antigen transported by wind currents 54 ; however, this possibility cannot be rigorously assessed until precise identification of the aetiological agents is achieved 29 .

SNPs influencing susceptibility

Although Kawasaki disease has been observed around the world and in multiple ethnic groups, geographical differences exist in incidence. The highest incidence is in Asian countries such as Korea and Japan, where it has increased over the past decades and is now 10–20 times more prevalent than in North America and Europe 30 . This increased susceptibility in Asian children, as well as in children with Asian ancestry living in North America 31 , indicates that genetic components predispose to disease susceptibility. In Japan, siblings of children with Kawasaki disease are at increased risk of developing the disease 55 . Single nucleotide polymorphisms (SNPs) in multiple genes have been associated with increased susceptibility to Kawasaki disease (Fig.  1 ); however, mechanisms linking those SNPs with Kawasaki disease progression are not yet well understood and require more investigation.

Calcium signalling pathway

Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC), a kinase that phosphorylates inositol 1,4,5-triphosphate (IP 3 ), is involved in many signalling processes in a wide array of cells. In T cells, IP 3 is released after T cell receptor stimulation, thus increasing levels of intracellular Ca 2+ through IP 3 receptors expressed on the endoplasmic reticulum and leading to nuclear translocation of nuclear factor of activated T cells (NFAT), IL-2 production and T cell activation 56 . By blocking the interaction of IP 3 with its receptor, ITPKC negatively regulates T cell activation. A functional SNP in ITPKC has been associated with increased risk of coronary artery lesions in Taiwanese 57 , Japanese and American patients with Kawasaki disease 58 . Mechanistically, this ITPKC polymorphism might directly contribute to T cell hyperactivity, and more importantly, it might promote NLRP3 inflammasome activation and increase production of IL-1β and IL-18 (ref. 59 ). ORAI1 is a membrane-bound Ca 2+ channel protein encoded by ORAI1 that is involved in the Ca 2+ –calcineurin–NFAT signalling pathway. Although no significant association between ORAI1  polymorphisms and Kawasaki disease susceptibility or IVIG treatment response was initially reported in the Taiwanese population 60 , an SNP in exon 2 of ORAI1 is associated with Kawasaki disease susceptibility in the Japanese population 61 , and interestingly this SNP is 20 times more frequent in the general Japanese population than in the general European population 61 . Another SNP in SLC8A1 , which encodes the Na + –Ca 2+ exchanger, is also associated with susceptibility to Kawasaki disease and aneurysm formation 62 , further highlighting the critical role of calcium signalling pathways in development of Kawasaki disease. Crucially, the Ca 2+ –NFAT signalling pathway is also key to intracellular Ca 2+ regulation and therefore to NLRP3 inflammasome activation and IL-1β production 63 , 64 .

CD40 ligand

CD40 ligand (CD40L) is a protein expressed by a large array of cells including activated T cells, B cells, monocytes and platelets. CD40L receptor, CD40, is expressed by antigen-presenting cells as well as endothelial cells 65 . CD40 engagement is associated with cell survival, activation, proliferation and cytokine production 65 . Compared with control patients with other febrile illnesses, patients with Kawasaki disease have increased CD40L expression on CD4 + T cells and platelets, which correlates with increased development of coronary artery lesions and is reduced by IVIG treatment 66 . An SNP in CD40L has been reported in Japanese patients with Kawasaki disease and is more frequent in male patients with coronary artery lesions than in female patients 67 . This polymorphism was not observed in a cohort of Taiwanese patients 68 ; however, another SNP in the CD40 gene has been reported in an independent cohort of Taiwanese patients and is associated with increased susceptibility to Kawasaki disease and development of coronary artery lesions 69 . These results indicate a role of the CD40–CD40L pathway in the development and severity of Kawasaki disease and highlight this pathway as a potential therapeutic target.

Mannose-binding lectin

Mannose-binding lectin (MBL), a pattern recognition molecule of the innate immune system, binds the surface of pathogenic organisms and activates the complement pathway 70 . A polymorphism in MBL2 was found to be an age-related risk factor for development of coronary artery lesions in a Dutch cohort of patients 71 , 72 . Another study in a cohort of Japanese patients with Kawasaki disease showed that codon 54 variants in MBL2 are significantly associated with susceptibility to Kawasaki disease 73 . Interestingly, in the Candida albicans water-soluble fraction (CAWS) mouse model of Kawasaki disease vasculitis, MBL-A and MBL-C deposition are observed in the aortic root, suggesting involvement of the MBL-dependent lectin pathway in this experimental model 74 . However, further studies are required to understand the pathogenic roles of those two proteins as well as their potential as therapeutic targets.

Fcγ receptors

Polymorphisms in genes encoding the receptors for the Fc portion of immunoglobulins, Fcγ receptors (FcγRs), have been associated with the development of autoimmune and infectious diseases 75 , 76 , 77 . As Kawasaki disease is considered an infectious disorder, several studies have investigated the potential association of FcγR SNPs with Kawasaki disease susceptibility and the development of coronary artery lesions. In a cohort of Dutch patients, no difference in FcγR SNP distribution was observed between healthy individuals and patients with Kawasaki disease, and no association was noted between SNPs in FcγR genes and Kawasaki disease susceptibility 78 . However, a later study with >2,000 patients with Kawasaki disease and 9,000 control patients from multiple independent cohorts across different populations highlighted a Kawasaki disease-associated polymorphism in the FCGR2A locus, which encodes FcγRIIA (CD32a), a member of the family of IgG receptors 79 . This polymorphism has important implications as the standard of care for Kawasaki disease is IVIG, a pool of plasma IgG that interacts with FcγRs on immune cells. Interestingly, 15–20% of patients with Kawasaki disease have IVIG-resistant disease and require another round of IVIG treatment or the use of adjunctive therapies 15 , 19 , 20 , 80 . The exact mechanisms by which IVIG mediates its therapeutic effect and how IVIG resistance develops remain unknown, and the potential involvement of this FcγRIIA polymorphism in IVIG resistance requires further investigation.

Pathophysiology of Kawasaki disease

The innate immune response.

The immune response associated with Kawasaki disease is complex and involves the activation and infiltration of the coronary artery wall by both innate and adaptive immune cells (Fig.  2 ). On the basis of studies of post-mortem tissue from patients with Kawasaki disease, Kawasaki disease vascular pathology has been classified into three sequential linked pathological processes 81 . Necrotizing arteritis develops in the first 2 weeks of the disease and is associated with neutrophilic infiltrations, which gradually destroy the coronary artery intima, media and some portions of the adventitia. Alarmins from the S100 protein family, which are present in the cytoplasm of neutrophils, monocytes and macrophages 82 , also participate in this inflammatory process. Concentrations of circulating S100A8/A9 heterodimers (calprotectin) and S100A12 are substantially higher in patients with Kawasaki disease during the acute phase than in control patients with other febrile illnesses and decline after IVIG treatment 83 , 84 , 85 . After the acute phase of Kawasaki disease, plasma concentrations of S100A8/A9 heterodimers only remain elevated in patients with giant CAAs 84 , highlighting its potential utility as a biomarker to monitor long-term persistence of inflammation. S100A12 also contributes to the acute inflammatory response by directly stimulating monocytes to produce IL-1β, which in turn activates coronary endothelial cells 85 . Necrotizing arteritis might result in the formation of CAAs and is followed by two other processes, subacute or chronic vasculitis and luminal myofibroblast proliferation (LMP), which occur simultaneously and might be observed for months to years after disease onset 81 . The inflammatory infiltrates are composed of CD8 + T cells, IgA + plasma cells, eosinophils and macrophages, which release pro-inflammatory cytokines contributing to cardiovascular pathology. Meanwhile, myofibroblasts, mainly derived from smooth muscle cells, and their matrix products progressively obstruct the coronary lumen 81 (Fig.  2 ). Persistent subacute and chronic vasculitis and LMP can lead to stenosis and thrombosis after acute illness 6 , 9 .

figure 2

The normal coronary artery is composed of three general layers: the tunica intima, tunica media and tunica adventitia. The intima is mainly composed of endothelial cells, the media of smooth muscle cells and the adventitia of loose connective tissue. In Kawasaki disease, necrotizing arteritis develops in the first 2 weeks of the disease and is associated with neutrophilic infiltration, which gradually destroys the intima, media and some portions of the adventitia of the coronary artery. CD8 + T cells, IgA + plasma cells, monocytes and macrophages compose the inflammatory infiltrate during subacute chronic arteritis. These cells release pro-inflammatory cytokines such as IL-1β and TNF, which contribute to luminal myofibroblast proliferation, in which myofibroblasts, mainly derived from smooth muscle cells, and their matrix products progressively obstruct the coronary lumen.

Matrix metalloproteinases

Matrix metalloproteinases (MMPs; zinc-dependent endopeptidases that degrade extracellular matrix components) are known to have an important role in both inflammation and tissue remodelling processes 86 . Increased expression and activity of a diverse set of MMPs has been demonstrated in acute Kawasaki disease 87 , 88 , 89 . The expression levels of MMP3 and MMP9, both known to mediate vascular smooth muscle cell migration and neointimal formation 90 , are increased in patients with Kawasaki disease 91 , and the circulating levels of these MMPs correlate with the development of CAAs in these patients 92 . MMP3 SNPs are also associated with the development of CAAs 88 , and this protease is considered to be a driving factor allowing IL-1-induced signalling to lead to migration of vascular smooth muscle cells and their transition to proliferating myofibroblasts 93 , 94 , 95 . Whereas MMP9 has been studied and implicated in elastin breakdown in the Lactobacillus casei cell wall extract (LCWE)-induced Kawasaki disease mouse model 96 , 97 , information about the role of MMP3 in this mouse model is lacking.

MicroRNAs (miRNAs; a class of small non-coding RNAs that regulate mRNA expression) are emerging as critical gene regulators in a host of cellular processes, including inflammation 98 . Of human coding genes, 60–70% are estimated to be regulated by miRNAs 99 . Several studies attempting to discover Kawasaki disease biomarkers have found that the miRNA profiles of serum exosome or coronary artery tissues are associated with acute Kawasaki disease 100 , 101 , 102 , 103 , 104 . These miRNAs include miR-23a 100 , 101 , 102 , 103 , miR-27b 100 , miR-223 (refs 100 , 101 , 102 , 103 ) and miR-145 (ref. 103 ). These miRNAs might provide clues as to the molecular mechanisms involved in the development of the cardiovascular lesions associated with Kawasaki disease. For example, miR-145 is highly expressed in vascular smooth muscle cells and has been reported to promote their switching to neointimal proliferating cells 105 , 106 and to regulate the transforming growth factor-β signalling pathway 103 . Increased levels of miR-23a contribute to cardiomyocyte apoptosis and may promote inflammatory responses by blocking macrophage autophagy activity 107 , 108 . However, improved understanding and characterization of the molecular and cellular mechanisms underlying the different roles of miRs during Kawasaki disease require further studies with animal models.


Most attention in Kawasaki disease research and clinical practice has focused on the development of CAAs and long-term complications of coronary artery stenosis and ischaemia 109 . However, the subacute and chronic inflammation of Kawasaki disease is also associated with the development of myocarditis 3 , 6 , 110 , 111 , 112 . Myocarditis has been described as the ‘hidden face of the moon’ in Kawasaki disease 110 . Reports indicate that myocarditis occurs frequently during acute Kawasaki disease 111 , and serial myocardial biopsy studies have documented that histological myocarditis develops in the majority of patients with Kawasaki disease, even in the absence of coronary aneurysms 113 , 114 . More recent data indicate that myocardial inflammation can be documented in 50–70% of patients using gallium citrate ( 67 Ga) scans and technetium-99 ( 99m Tc)-labelled white blood cell scans 115 . Another study has shown that myocardial inflammatory changes and myocardial oedema in Kawasaki disease occur even before coronary artery abnormalities and without concurrent ischaemic damage 112 .

Myocarditis in Kawasaki disease tends to develop early, and acute left ventricular dysfunction is generally transient and responds readily to anti-inflammatory treatment 116 . However, Kawasaki disease myocarditis might be associated with fatal arrhythmias in infants, and in certain cases might lead to long-term complications including myocardial fibrosis 81 , 117 . Therefore, myocarditis during Kawasaki disease and its potential consequences deserve serious investigation, and long-term studies into late adulthood are needed.

Complement and immune complexes

Kawasaki disease affects small and medium sized vessels, particularly the coronary arteries; however, dilatations and aneurysms can occur systemically, including in the axillary, subclavian, brachial, renal and iliac arteries as well as the abdominal aorta 23 , 118 , 119 , 120 . Post-mortem findings have revealed that 73% of patients with Kawasaki disease have renal artery involvement and acute kidney injury 121 involving glomerulonephritis with intracapillary changes and deposition of immune complex composed of IgA and complement component 3 (C3) 22 , 122 , 123 . These findings are comparable to those in two other human vasculitis diseases, IgA vasculitis (IgAV) and IgA nephropathy (IgAN), which are similarly characterized by IgA immune complexes with C3 deposition in kidney glomeruli (see below). Increased concentrations of circulating IgA and secretory IgA (sIgA) have been reported in the serum of children with Kawasaki disease during the acute phase 124 . IgA + plasma cells are present in the coronary artery wall and in non-vascular tissues, such as the kidney, trachea and pancreas of patients with Kawasaki disease 25 , 26 . This IgA response is oligoclonal, seems to be antigen driven and might be caused by Kawasaki disease-triggering agents 125 , 126 .

The IL-1 signalling pathway

Evidence from mouse models of Kawasaki disease 11 , 127 , 128 , as well as transcriptome analysis performed on whole blood of patients with Kawasaki disease during the acute or convalescent phase 129 , 130 , demonstrate the involvement of innate immune cells and inflammasome overactivation throughout the acute phase of the disease. In vitro cultured PBMCs isolated from patients with Kawasaki disease spontaneously release IL-1β into the supernatant, and this process is substantially reduced after IVIG treatment 28 . Serum concentrations of both IL-1β and IL-18 are also higher in children with acute Kawasaki disease than in control patients with other febrile illnesses, and markedly decrease during the convalescent phase 59 , supporting the concept of activation of the NLRP3 inflammasome complex. Similarly, IL-1 and NLRP3-related gene transcripts are upregulated in PBMCs from patients with acute Kawasaki disease and are decreased during the convalescent phase of the disease 59 , and an IL1B -gene-related signature is associated with acute phase disease and IVIG resistance 130 . Furthermore, a study has shown that differential expression of IL-1β and related signalling genes might have a role in mediating the sex-based differences seen in patients with Kawasaki disease 131 . In the LCWE mouse model of Kawasaki disease, the activation of caspase 1, IL-1α and IL-1β is key to the development of coronary arteritis, aneurysms, myocarditis and abdominal aorta aneurysms 127 , 128 , 132 . IL-1 has the capacity to expand and promote the differentiation of antigen-specific CD8 + T cells 133 , and indeed the frequencies of circulating CD4 + and CD8 + T cells are increased in patients with Kawasaki disease 134 . Infiltrations of mature dendritic cells as well as activated cytotoxic CD8 + T cells have been reported in arterial layers of coronary aneurysms 24 , 135 . Therefore, blocking the NLRP3–IL-1β pathway seems to be a valid therapeutic option in Kawasaki disease.

Role of the gastrointestinal tract

Intestinal permeability.

The intestinal barrier has a critical role in maintaining intestinal homeostasis and health by preventing harmful organisms and luminal antigens from entering the circulation. A dysfunctional intestinal barrier, characterized by increased intestinal permeability, is recognized as a pathogenic factor in many inflammatory diseases 136 . In Kawasaki disease, abdominal pain, diarrhoea and vomiting are often observed at the onset of acute illness, affecting up to 60% of diagnosed patients and indicating that the gastrointestinal tract is also affected 4 , 137 , 138 , 139 , 140 . A multicentre study of >300 patients revealed that gastrointestinal manifestations at onset of disease complicate diagnosis, delay adequate treatment and correlate with IVIG resistance and severity of CAAs 141 . Immunohistochemical studies have revealed higher numbers of activated CD4 + T cells and macrophages along with lower numbers of CD8 + T cells in the jejunum lamina propria in patients with Kawasaki disease than in control patients with diarrhoea from cows’ milk protein intolerance 142 . However, these cellular abnormalities are specific to the acute phase of the disease and return to normal during the convalescent phase 142 . IgA + plasma cells have also been observed in a variety of different vascular and non-vascular tissues in patients with Kawasaki disease 26 , and patients with Kawasaki disease also have increased concentrations of sIgA, which is produced at the intestinal mucosal surface, in their serum 124 . These studies indicate that the gastrointestinal tract is affected during Kawasaki disease and that mucosal immune activation might compensate and protect from defective intestinal barriers.

The role of gut-related immunity in the induction of inflammation in organ systems distant from the gut has been the subject of intensive investigation. We have observed increased intestinal permeability and a dysregulated intestinal immune response characterized by increased numbers of IgA + B cells in the Peyer’s patches in the LCWE-induced mouse model of Kawasaki disease 143 (Fig.  3 ). In this model, the excessive IL-1β release associated with LCWE injection acts on intestinal epithelial cells to open tight junctions, and administration of IVIG or pharmacological agents that block intestinal permeability significantly reduces disease development 143 . Altogether, these observations link increased intestinal permeability and defective intestinal barrier function with systemic IL-1β release in Kawasaki disease.

figure 3

In healthy individuals, intestinal epithelial cells are sealed together by intestinal tight junctions, and the intestinal epithelium acts as a barrier that prevents the passage of commensal bacteria and pathogens while permitting intercellular flux of ions, molecules and metabolites. Lactobacillus casei cell wall extract (LCWE)-induced Kawasaki disease vasculitis and human Kawasaki disease are associated with increased IL-1β production, which leads to decreased expression of intestinal tight junctions, resulting in increased intestinal permeability. Differences in intestinal microbiota composition have been observed in patients with Kawasaki disease, and intestinal dysbiosis might contribute further to the inflammatory process. LCWE injection is also associated with a dysregulated intestinal immune response characterized by increased numbers of IgA + B cells in the gastrointestinal tract and elevated secretory IgA (sIgA) concentrations. Intestinal barrier dysfunction results in sIgA leakage to the systemic circulation and pathogenic IgA–C3 immune complex deposition in the vascular tissues.

The intestinal microbiome

Despite the strong connection between the intestinal microbiome and development of cardiovascular diseases 144 , 145 , only a few studies have investigated the role of the intestinal microbiome during development of Kawasaki disease or treatment resistance. Microbiological culture-based methods demonstrated that, compared with healthy control individuals, patients with Kawasaki disease have a different intestinal microbiota composition characterized by a lower incidence of the Lactobacillus genus 146 , 147 and increased Streptococcus and Staphylococcus 148 species. Lactobacilli have been reported to prevent diarrhoeal disorders 149 , 150 and to improve intestinal barrier function by increasing the expression of intestinal tight junctions 151 , 152 , enhancing the intestinal mucus layer 153 and modulating the intestinal microbiota composition 154 . Lactobacilli have also been shown to boost innate and immune functions against a variety of bacterial infections 155 , 156 , 157 , and their disappearance during acute Kawasaki disease might lead to the blooming of other bacterial pathogens, which might further promote intestinal barrier dysfunction and inflammation. Intriguingly, a retrospective study of 364 patients with Kawasaki disease showed that children who received microbiome-altering antibiotics in the week before Kawasaki disease diagnosis were substantially more likely to have IVIG-resistant disease than those who did not receive antibiotics 158 . Antibiotics alter the abundance, taxonomic richness and diversity of the bacterial 159 , 160 as well as fungal 161 intestinal microbiome, and those alterations might persist from weeks to years after treatment discontinuation 159 , 160 , 162 . A longitudinal metagenomic study of faecal samples derived from patients with Kawasaki disease showed a marked increase of five Streptococcus spp. during the acute phase of Kawasaki disease 163 ; however, all patients in that study were treated with antibiotics in the early stage of disease, therefore this observation might be reflective of antibiotic-induced dysbiosis and not Kawasaki disease itself. Nonetheless, how this intestinal dysbiosis occurs and how its effect on intestinal permeability affects the development of cardiovascular lesions during Kawasaki disease vasculitis remains unknown and under-appreciated.

Link with IgA vasculitis

IgAV, or Henoch-Schönlein purpura, is an IgA-mediated necrotizing vasculitis resulting in fibrinoid destruction of the affected small vessels. Renal involvement, characterized by IgA deposition in the kidney glomeruli, is also observed in IgAV 164 . IgAV nephritis is closely related to another glomerular disease, IgAN, wherein accumulation and deposition of IgA and IgA immune complexes in the kidney glomerular mesangium drive glomerular inflammation 165 . As IgA is mainly found at mucosal surfaces, a ‘gut–kidney axis’, influenced by a mix of genetic, microbial and dietary factors, has been suggested to be involved in the development of both IgAN 166 and IgAV in paediatric and adult patients 167 . We have demonstrated that the LCWE-induced mouse model of Kawasaki disease vasculitis is associated with the deposition of IgA and IgA–C3 immune complexes in vascular tissues, such as the inflamed coronary artery and abdominal aorta 143 . Deposited IgA and IgA–C3 immune complexes might result in overactivation of the immune cells present in the cardiovascular lesions and subsequent amplification of inflammation 143 . Substantial evidence indicates that immune complexes might promote vascular damage during human Kawasaki disease through the activation and aggregation of platelets, the release of vasoactive mediators, and the subsequent recruitment of neutrophils and leukocytes to the site of inflammation (reviewed elsewhere 168 ).

Interestingly, we have also observed IgA and C3 deposition in the kidney glomeruli of LCWE-injected mice developing Kawasaki disease 143 , and immune complex-mediated nephropathy has also been observed in Kawasaki disease 123 . However, to date IgA deposition has not been reported in CAAs of patients with Kawasaki disease. Given that availability of human tissue samples is limited, and those that are available are usually collected at the end stage of the disease, they might not be representative of active Kawasaki disease pathological features, and further studies are warranted. Like Kawasaki disease, IgAV develops mostly in children, affects males more than females, is more predominant in Asian countries such as Japan and Korea, and is also associated with abdominal pain, diarrhoea, skin rash and IgA deposition in the affected small vessels 169 . IgAN also shares pathological features with Kawasaki disease, such as increased intestinal permeability, low to moderate intestinal inflammation associated with activation of inflammatory cells in the small intestinal mucosa and colocalization of sIgA-complement in the glomerular mesangium 165 , 170 . Moreover, a polymorphism in the promoter of the lipopolysaccharide (LPS) receptor CD14 (CD14/159) is associated with coronary artery abnormalities in patients with Kawasaki disease 171 and has been linked to progression of IgAN to more severe renal disease 172 . IL-1β has a key pathogenic role during Kawasaki disease and also seems to be implicated in renal complications related to IgAV 173 and IgAN 174 . Altogether, given that Kawasaki disease shares clinical features and pathological mechanisms with both IgAV and IgAN, it is possible that Kawasaki disease is a form of IgAV. Similarly, treatments that have shown efficacy in Kawasaki disease, such as anakinra and IVIG, might be suitable and useful for treating IgAV 175 and IgAN.

Mouse models of Kawasaki disease

The lack of identification of specific aetiological agents and incomplete understanding of the molecular mechanisms involved in Kawasaki disease cardiovascular pathology have delayed the development of targeted and effective treatment options for this disease. In addition, the limited availability of tissue samples from patients with Kawasaki disease has considerably impeded progress in understanding the pathogenesis of the disease, making the availability of relevant animal models of Kawasaki disease extremely valuable. Kawasaki disease vasculitis can be induced in mice by injection of cell wall components from L. casei 176 , C. albicans 177 or nucleotide-binding oligomerization domain containing 1 (Nod1) ligand 178 (Table  1 ). These mouse models of Kawasaki disease have accelerated research and have enhanced understanding of the pathogenesis of this disease. However, no animal model perfectly recapitulates human disease. Particularly in the context of Kawasaki disease, given that the aetiology remains unknown, researchers must exercise caution in interpreting results based on experimental models and confirm findings in patient cohorts. Nevertheless, even though the extrapolation of preclinical mouse data to humans is far from straightforward, mouse models are still invaluable tools to study certain pathological aspects of human inflammatory diseases and gain mechanistic insights.

The LCWE mouse model

L. casei is a Gram-positive bacteria that colonizes the gastrointestinal and urogenital tracts of both human and animals 179 . More than 35 years ago, Lehman et al. 180 demonstrated that a single intraperitoneal injection of LCWE induces a dose-dependent and chronic polyarthritis in rats. However, when injected into mice, LCWE induces instead a focal coronary arteritis 176 . How and which element of LCWE triggers Kawasaki disease vasculitis is unknown. LCWE is mainly composed of peptidoglycans, contains high levels of rhamnose and is resistant to lysozyme degradation 176 .

The cardiovascular lesions induced in mice by LCWE are histologically similar to those observed in human disease. LCWE-induced Kawasaki disease vasculitis is characterized by infiltration of inflammatory cells in the aortic root, development of necrotizing arteritis in the coronary artery followed by luminal obstruction due to LMP that can lead to complete coronary artery stenosis 181 , recapitulating the three pathological processes of human Kawasaki disease described above (Fig.  4a – d ). In children with Kawasaki disease, thrombotic occlusion of the inflamed coronary artery leads to ischaemic heart disease 23 , 120 , and similarly, occluding organizing thrombus in the coronary artery can be observed in LCWE-injected mice (Fig.  4e ). Acute myocarditis and chronic scarring of the coronary arteries with the formation of stenotic fragments are also observed in LCWE-induced Kawasaki disease vasculitis (Fig.  4f ), even long after the acute phase 182 , which is similar to the fibrotic lesions that might lead children with Kawasaki disease to develop long-term cardiovascular sequelae in adulthood 8 , 9 . MRI and echocardiography in LCWE-injected mice demonstrate the presence of electrocardiographic changes (as observed in human Kawasaki disease) and myocardial dysfunction, which are responsive to anakinra therapy 183 , 184 .

figure 4

Wild-type mice underwent intraperitoneal injection with Lactobacillus casei cell wall extract (LCWE), and heart tissues were harvested 2 weeks later. Haematoxylin and eosin (H&E) and trichrome staining were performed on heart sections. a | Inflammatory cell infiltration in the aortic route (H&E staining; ×40). b | Arteritis development in epicardial muscular coronary artery (H&E staining; ×20). c | Luminal myofibroblast proliferation (LMP) and non-specific neointimal proliferation injury to the arterial wall (trichrome staining; ×200). d | Complete occlusion of the coronary artery by LMP (trichrome staining; ×20). e | Organized thrombus in the coronary artery (H&E staining; ×200). f | Myocarditis (H&E staining; ×200). Ao; aorta, CA; coronary artery.

The LCWE-induced Kawasaki disease vasculitis in mice is dependent on intact TLR2 and MyD88 signalling and the subsequent release of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF 10 . Genetic depletion of the TNF receptor or pharmacological blockade of the TNF signalling pathway (with infliximab (monoclonal antibodies to TNF) or etanercept (soluble TNF receptors)) protects mice from LCWE-induced Kawasaki disease vasculitis 132 , 185 . This model is also T cell dependent, as Rag1 –/– mice develop fewer cardiovascular lesions 11 . CD8 + T cells are specifically required for LCWE-induced Kawasaki disease vasculitis as treatment of LCWE-injected mice with an anti-CD8-depleting antibody prevents the development of vasculitis 181 . This finding correlates with human disease, in which infiltrations of CD3 + T cells 135 , and particularly CD8 + T cells, are detected in the CAAs 24 . The LCWE model has also confirmed the importance of the ITPKC pathway in Kawasaki disease development and demonstrated that ITPKC deficiency is associated with increased Ca 2+ flux and levels of IL-1β in vitro 59 . Interestingly, the relatively mild development of coronary arteritis in LCWE-injected CBA/N mice — which are characterized by a defective B cell maturation process and poor humoral immune responses — suggests that the humoral immune response might participate in amplification of the disease 186 . IgA + plasma cells infiltrate vascular and non-vascular tissues during the acute phase of Kawasaki disease 25 , 26 , resulting in the development of an oligoclonal IgA response in the coronary artery 125 , 126 . Interestingly, we have observed increased numbers of IgA + plasmablasts in the spleen, Peyer’s patches and abdominal aorta draining lymph nodes of LCWE-injected mice, as well as increased concentrations of circulating IgA and IgA deposition in heart tissues, abdominal aorta and kidney glomureli 143 .

Mouse models also provide a useful opportunity to evaluate the efficacy of therapeutic regimens on the development and healing of cardiovascular lesions. When given up to 5 days after LCWE injection, IVIG substantially decreases the severity of cardiovascular lesions in mice 187 , mirroring the effects of IVIG treatment in humans. As described above, IL-1β signalling is higher in patients with Kawasaki disease than in age-matched control patients with other febrile illnesses 91 , 188 , and studies using the LCWE model helped lead to the discovery of the importance of this pathway in the pathogenesis of the disease and the therapeutic potential of IL-1 blockade. Depletion of macrophages or blocking the IL-1 pathway either genetically using IL1R −/− , IL1α −/− or IL1β −/− mice or with antibodies targeting IL-1α or IL-1β, or anakinra (IL1Ra), strongly reduces cardiovascular lesion development as well as myocardial dysfunction in LCWE-injected mice 128 , 132 , 184 .

The CAWS mouse model

C. albicans is a harmless commensal fungus normally present in the human gastrointestinal tract that can transition into a pathogen capable of inducing inflammation in immune-impaired hosts. In 1979, Murata demonstrated that an alkaline extract made from C. albicans isolated from faeces from a patient with Kawasaki disease induced coronary arteritis in mice 177 . CAWS is composed of polysaccharides, mainly β-glucans and α-mannan proteins of the yeast cell wall 189 , and needs to be injected intraperitoneally for five consecutive days in the first week of the disease to induce vasculitis in the aortic valves and the coronary arteries 189 , 190 . In this model, recognition of α-mannan proteins by the dectin-2 receptor seems to be essential, as CAWS-injected Dectin-2 −/− mice do not develop vasculitis 191 .

The CAWS model shares some histological similarities with human Kawasaki disease pathology in that inflammation affects both the aortic root and the proximal region of the coronary arteries 190 . Inflammation can also affect non-coronary artery sites in 25% of CAWS-injected mice and can be observed in the lymph nodes, the kidneys and the liver 190 , 192 . CAWS-induced coronary artery lesions resemble those of human Kawasaki disease and are typically proliferative, granulomatous and characterized by intimal thickening with destruction of the elastic lamina and media 190 . Echocardiography in CAWS-injected mice indicates a marked decrease of cardiac function, which can be restored by IL-10 supplementation 193 . IL-10 is a potent anti-inflammatory cytokine that might improve the outcome of CAWS-induced vasculitis by inhibiting the release of pro-inflammatory mediators, such as TNF and IL-1β, from tissue-infiltrating innate immune cells 194 . Interestingly, CAWS-induced Kawasaki disease vasculitis is also strain dependent, as CAWS injections lead to a high incidence of vasculitis in CD-1, C3H/HeN, DBA/2 and C57BL/6N mice, but the CBA/JN strain is resistant to coronary arteritis 190 , 195 . The DBA/2 strain is the most sensitive, with the highest mortality rate resulting from a more intense coronary arteritis 195 . The sensitivity of DBA/2 mice is associated with increased production of the pro-inflammatory cytokines TNF, IL-6 and IFNγ 195 , 196 , whereas resistance of CBA/JN mice is explained by increased levels of IL-10 production in that strain 197 .

Despite the presence of T cell and B cell infiltration in the inflamed coronary artery, mice lacking T cells still develop moderate to typical cardiac inflammation, indicating that T cells might not be required in the development of Kawasaki disease vasculitis in this particular model 198 , 199 . Absence of both T cells and B cells in Rag1 −/− mice leads to lower incidence of CAWS-induced Kawasaki disease vasculitis; reconstitution of Rag1 −/− mice with wild-type, but not CCR2 −/− , T cells and B cells restores cardiovascular lesions, suggesting roles for both T cells and B cells and the modulation of disease development by CCR2 expression 200 . The innate immune response also participates in vasculitis development; resident macrophages recognize the CAWS antigens through the dectin-2 receptor, leading to their activation, release of CCL2, and recruitment of neutrophils and inflammatory monocytes producing IL-1β in the aortic root 201 .

CAWS-induced vasculitis is also associated with the rapid production of granulocyte–monocyte colony-stimulating factor in the heart, which subsequently drives inflammatory myocarditis by activating tissue macrophages and promoting recruitment of neutrophils and monocytes 199 . TNF is also produced during the acute phase of CAWS-induced Kawasaki disease vasculitis and is essential for the development of acute myocarditis, as TNF receptor-deficient mice are protected from the development of CAWS vasculitis 202 . IVIG administration substantially reduces CAWS-induced heart vessel inflammation 203 . Like the LCWE model, the CAWS model is also dependent on the IL-1 pathway, as IL1R −/− , IL1β −/− , Asc −/− and Nlrp3 −/− mice are protected from induction of vasculitis, and treatment with anti-IL-1β agents substantially attenuates CAWS vasculitis 202 , 204 , 205 .

The Nod1 ligand mouse model

Endothelial cells are equipped to sense microbial components through Toll-like receptors and nucleotide-binding oligomerization domain-containing protein like receptors. Subcutaneous injection or oral delivery of FK565, a specific synthetic Nod1 ligand, in mice primed with LPS results in a diffuse cellular inflammation of the aortic root and transmural infiltration of inflammatory cells in the coronary artery wall 178 , 206 . Other arteries, such as the iliac and renal arteries, also show signs of inflammation associated with a thickening of the intima 206 .

The mechanisms by which FK565 induces coronary arteritis in mice remain unknown. When administered orally, FK565 does not induce intestinal mucosa inflammation, but specifically activates vascular cells to produce a diverse array of pro-inflammatory cytokines, including IL-1β 206 , and chemokines such as CCL2, resulting in the recruitment of inflammatory cells in the tissues 178 . This model seems to be independent of T cells, B cells and natural killer T cells, as LPS-primed Rag-1 −/− mice still develop aortitis and coronary arteritis after FK565 injection 207 . The inflammatory infiltrates observed around the inflamed aortic root and coronary arteries mainly comprise neutrophils and CD11c + cardiac macrophages; their specific depletion considerably reduces the development of FK565-induced Kawasaki disease vasculitis 178 , 207 . The concentration of circulating IL-1β is substantially increased in the serum of FK565-injected mice compared with control or CAWS-injected animals, and higher IL-1β levels correlate with a larger inflammation area 206 . However, specific studies further investigating the role of IL-1β in this model are needed.

Treatment of Kawasaki disease

Traditional and novel therapies in humans.

The current standard of care for Kawasaki disease is the use of high-dose IVIG together with aspirin. If given during the first 10 days of the disease, IVIG reduces the risk of development of coronary arteritis and aneurysms from about 30% to 5–7% 14 , 15 . The mechanisms by which IVIG treatment reduces the inflammatory responses are still unknown; however, IVIG is suspected to have a wide spectrum of action targeting multiple arms of the immune response 18 . IVIG has been shown to inhibit IL-1β production from in vitro stimulated macrophages and to stimulate the production of IL-1Ra 208 , 209 . During Kawasaki disease, IVIG reduces production of inflammatory cytokines and chemokines, and decreases the activation and number of circulating neutrophils, monocytes, macrophages and activated T cells by saturating Fc receptors 18 . The majority of patients with Kawasaki disease who are treated with IVIG improve and do not develop coronary artery damage; however, up to 20% of children with Kawasaki disease do not respond to treatment or have fever recurrence after initial IVIG treatment, and these patients are at the highest risk of developing coronary artery lesions 3 , 20 , 210 .

The involvement of pro-inflammatory cytokines in the acute phase of Kawasaki disease suggests that combinational therapy, composed of IVIG associated with TNF inhibitors, steroids, calcineurin inhibitors or anakinra, might be useful to treat patients with IVIG-resistant disease. The use of TNF inhibitors in combination with IVIG has had mixed results thus far. Infliximab was associated with decreased fever duration and reduced markers of inflammation (C-reactive protein and neutrophil counts), suggesting a possible improvement of coronary artery outcomes 211 ; however, etanercept treatment resulted in a substantial reduction in IVIG resistance only in patients >1 year old 212 .

An important area of research is the use of biomarkers to predict IVIG resistance in Kawasaki disease. The Kobayashi scoring system, based on a combination of laboratory test results (for example, C-reactive protein levels, neutrophil percentages, platelets counts and levels of aspartate and alanine aminotransferase) and demographic variables (sex, age and number of days of illness before the start of the treatment) has been successfully used to predict IVIG-resistance in Japanese patients 213 , but not in North American children with Kawasaki disease 214 . The combination of prednisolone and IVIG to treat Japanese patients with Kawasaki disease predicted to have IVIG-resistant disease according to the Kobayashi score (RAISE study) resulted in more rapid fever resolution, reduced development of CAAs and lower incidence of additional rescue treatment 215 compared with IVIG alone.

As discussed above, Kawasaki disease susceptibility and increased coronary artery lesion risk are associated with an SNP in ITPKC 58 that results in a lack of NFAT regulation and activation of the T cell compartment owing to increased IL-2 production 216 . CD8 + cytotoxic T cells are present in the inflamed arterial wall during Kawasaki disease 24 , 135 ; therefore, targeting T cell expansion might be an efficient approach to preventing CAAs during Kawasaki disease. A combination treatment of IVIG and ciclosporin, a calcineurin inhibitor that suppresses IL-2 production and T cell activation, was tested in a clinical trial in Japanese patients with Kawasaki disease predicted to have IVIG-resistant disease based on the Kobayashi score (KAICA trial) 217 . In this trial, the combination treatment was shown to be safe and associated with a lower incidence of CAAs; however, treatment was linked with increased risk of relapse 217 . Furthermore, the scoring system used to identify IVIG-non-responders is poorly predictive in European children with Kawasaki disease, limiting the conclusions of this study.

The important role of the IL-1β–IL-1 receptor pathway in Kawasaki disease development has been demonstrated in both human patients 27 , 28 , 129 , 130 and mouse models 127 , 132 , 202 , 204 . Therefore, clinical trials investigating IL-1 pathway inhibition by using anakinra, which blocks both IL-1α and IL-1β, have been initiated in North America (ANAKID; ClinicalTrials.gov identifier NCT02179853) 218 and Europe (Kawakinra; European Clinical Trials number 2014-002715-4) 219 . Already, multiple case reports exist of the successful use of anakinra to treat patients with IVIG-resistant Kawasaki disease 220 , 221 , 222 , 223 , 224 , indicating the promise of this second-line therapy.

Therapeutic insights from mouse models

Although no animal model can fully mimic human disease, the LCWE-induced Kawasaki disease mouse model has been accepted by many in the research community as a reliable experimental model providing novel insights that can be tested in patients. For example, IVIG efficiently prevents coronary arteritis development in LCWE-injected mice 187 as well as in the CAWS mouse model of Kawasaki disease 203 .

The effects of the calcineurin inhibitors ciclosporin and tacrolimus have been investigated in the Nod1 ligand-induced mouse model of Kawasaki disease vasculitis 225 . This approach was rational given the established role of T cells and calcium signalling in Kawasaki disease. However, contrary to the expected outcome, these inhibitors exacerbated the coronary arteritis 225 . Notably, however, this result was probably related to the choice of mouse model, as the Nod1 ligand-mediated mouse model of Kawasaki disease vasculitis has previously been shown to be T cell-independent 207 . Indeed, in an independent study using the CAWS mouse model, which is T cell dependent, ciclosporin suppressed CAWS-induced vasculitis 226 , emphasizing the importance of model selection in preclinical studies. Most importantly, results in human studies bear out the therapeutic potential of calcineurin inhibition, as the Japanese phase III trial (KAICA trial) showed that adding ciclosporin to IVIG in patients with Kawasaki disease who were at high risk of IVIG resistance was beneficial in diminishing overall incidence of CAAs 217 .

The role of TNF has been investigated in both the LCWE and the CAWS mouse models of Kawasaki disease vasculitis 185 . Initially, etanercept treatment or genetic deletion of TNF receptor 1 was shown to protect mice from LCWE-induced coronary arteritis 185 , 202 . Infliximab treatment also prevented the development of both LCWE-induced coronary arteritis and myocarditis 132 . Similar results were obtained in the CAWS mouse model of Kawasaki disease vasculitis, in which etanercept 226 , 227 suppressed the incidence and decreased the severity of vasculitis. Mechanistically, TNF has been proposed to be produced by myeloid cells in the acute phase and to promote myocarditis and recruitment of immune cells by acting on cardiac stromal cells 202 . However, infliximab and etanercept might not directly target the TNF signalling pathway, and their observed effects might be indirect. Indeed, infliximab is not able to bind mouse TNF 227 , 228 ; therefore, the anti-inflammatory effect of infliximab might be attributable to the binding of Fc receptors at the surface of activated cells 229 , 230 .

The overwhelming evidence for the critical role of IL-1β in promoting LCWE-induced Kawasaki disease vasculitis in mice 127 , 128 , 132 led to the initiation of clinical trials testing the effect of anakinra for blocking IL-1β as a second therapy option to treat children with IVIG-resistant Kawasaki disease. Multiple case reports now outline the successful use of anakinra to treat patients with IVIG-resistant Kawasaki disease 221 , 222 , 223 , 224 . Alternatively, direct inhibition of the NLRP3 inflammasome might be a more targeted therapeutic strategy to treat Kawasaki disease, as it would affect several pathways beyond IL-1β, including IL-1α and IL-18. Several NLRP3 inhibitors have been identified 231 and tested in mouse models of inflammatory diseases, such as experimental autoimmune encephalomyelitis and cryopyrin-associated periodic syndrome 232 . It would be interesting to determine if such drugs could be used to prevent and reduce the cardiovascular complications in mouse models of Kawasaki disease vasculitis.


Over the past 40 years, research has improved our understanding of Kawasaki disease pathology and the development of coronary vasculitis. However, some questions still remain unanswered, such as the identification of the aetiological agents, how the disease is triggered, and the specific immune pathways associated with coronary vasculitis development and IVIG resistance. Owing to the rarity of human tissues from patients with Kawasaki disease, the use of animal models reproducing human Kawasaki disease features is invaluable. Many advances have been made over the decades by combining biological observations in human samples with mechanistic insights from experimental animal models. This ‘bench to bedside’ approach successfully led to the identification of the critical role of IL-1β in Kawasaki disease and resulted in the development of clinical trials in which anakinra is being used to treat children with IVIG-resistant Kawasaki disease.

LCWE-injected mice exhibit a dysfunctional intestinal barrier, and the increased IgA response and elevated sIgA levels in both LCWE-injected mice and children with Kawasaki disease reveal the existence of a ‘gut–vascular’ axis 143 . In evaluating this model system and the role of IgA, it should not be forgotten that injection of identically prepared LCWE induces chronic polyarthritis in selected inbred rat strains 180 , 233 . This observation implies that a common immunogenetic pathway might underlie a variety of autoimmune illnesses, with disease expression moderated not by the inducing agent, but rather by host genetics. The fact that cell wall fragments of common gut bacteria can produce varying disease manifestations in the face of inflammation-induced increased gut permeability suggests that some autoimmune diseases might not in fact be induced by the normal response to an unusual agent, but rather an unusual response to a common agent. Similarly, we hypothesize that vasculitic diseases, including Kawasaki disease, are not a usual response to an unusual environmental stimulus, but rather an unusual response (genetically determined) to a common environmental stimulus. This hypothesis has major implications for understanding the aetiology and pathogenesis of not only Kawasaki disease but also IgA-mediated diseases and perhaps others. In addition, it strongly suggests that inhibition of IL-1β might be effective for the many chronic inflammatory diseases in which IgA deposition is a key finding.

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The work of M.A. is supported by the NIH Grant R01 AI072726 and M.N.R. is supported by the NIH grant R01 HL139766.

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Noval Rivas, M., Arditi, M. Kawasaki disease: pathophysiology and insights from mouse models. Nat Rev Rheumatol 16 , 391–405 (2020). https://doi.org/10.1038/s41584-020-0426-0

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Diagnosis, Progress, and Treatment Update of Kawasaki Disease

Ho-chang kuo.

1 Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; wt.moc.oohay@84oukcire

2 Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan

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Kawasaki disease (KD) is an acute inflammatory disorder that primarily affects children and can lead to coronary artery lesions (CAL) if not diagnosed and treated promptly. The original clinical criteria for diagnosing KD were reported by Dr. Tomisaku Kawasaki in 1967 and have been used for decades. However, research since then has highlighted the limitations of relying solely on these criteria, as they might lead to underdiagnosis or delayed diagnosis, potentially increasing the risk of coronary artery complications. This review appears to discuss several important aspects related to KD diagnosis and management. The current diagnostic methods for KD might need updates, especially considering cases that do not fit the typical clinical criteria. Recognizing diagnostic pitfalls and distinguishing KD from other conditions that might have similar clinical presentations is essential. The differences and similarities between KD and Multisystem Inflammatory Syndrome in Children (MIS-C), another inflammatory condition that has been associated with COVID-19, were also reviewed. The review explores the potential role of eosinophil count, new biomarkers, microRNA panels, and scoring systems in aiding the diagnosis of KD. Overall, the review article provides a comprehensive overview of the evolving landscape of KD diagnosis and management, incorporating new diagnostic methods, biomarkers, and treatment approaches to improve patient outcomes and reduce the risk of complications.

1. Introduction

Kawasaki disease (KD) was first described by Japanese pediatrician Dr. Tomisaku Kawasaki in 1967 in a Japanese-language journal and later in 1974 in an English-language journal. He observed a 4-year-old boy who exhibited a range of clinical symptoms, including a persistent high-grade fever and a skin rash. Initially, he referred to this condition as “acute febrile mucocutaneous lymph node syndrome” (MCLS). Although the new diagnosis faced initial skepticism, Dr. Kawasaki persisted. After collecting a series of 50 cases, he published his findings, accompanied by meticulous hand-drawn diagrams, in a Japanese medical journal. Dr. Kawasaki outlined the key features of this newly discovered disease, which included persistent fever, bilateral non-purulent conjunctivitis, diffuse oral fissures, a distinctive skin rash, edema of the hands and feet, as well as lymphadenopathy of the neck [ 1 ]. The diagnosis and treatment of KD need updating, including criteria comparison, the importance of eosinophils, novel markers and techniques for diagnosis, the potential role of hydrogen gas inhalation in coronary artery lesions (CAL), and precise treatment to prevent CAL formation.

2. Clinical Features and Diagnosis Criteria Comparison of Kawasaki Disease

Even though the initial name for this novel inflammatory disease was eventually altered to “Kawasaki disease” as a tribute to him, his original depiction of the condition still closely aligns with the current diagnostic criteria. Apart from Japan, the most widely adopted diagnostic criteria for KD are those established by the American Heart Association (AHA). These criteria encompass a fever lasting for at least 5 days (above 38 °C) and the presence of at least 4 out of the following 5 major clinical criteria [ 2 ]: bilateral conjunctival injection without discharge, changes in the oral mucosa (including fissured lips, strawberry tongue, or a red pharynx), alterations in the peripheral extremities (such as redness of the palms and soles, acute-phase edema of the hands and feet, and peeling of the skin around the nails after the acute phase), a diverse rash, and cervical lymphadenopathy (always with a size exceeding 1.5 cm in diameter) [ 2 ].In Japan, the diagnostic criteria for KD established by the Japanese Ministry of Health are primarily employed, and they exhibit minor variations. Notably, in contrast to the AHA criteria, the presence of fever for at least 5 days is not deemed an obligatory criterion under the Japanese guidelines. Put differently, individuals who display all five cardinal symptoms but are either without fever or have a fever lasting fewer than 5 days (1, 2, 3, or 4 days) can still receive a KD diagnosis based on the Japanese criteria [ 3 ].The comparison of different diagnostic criteria is presented in Table 1 . Based on these diagnostic standards, we have developed the “Kuo’s 1-2-3-4-5 mnemonic,” a convenient memory aid for the five major KD criteria, as demonstrated in Table 2 . In a 2017 update to the diagnostic guidelines for KD, the AHA acknowledged the ongoing discussion regarding fever duration. The AHA mentioned that KD can now be diagnosed in patients with a fever lasting a minimum of 4 days (as opposed to the previous requirement of 5 days), provided they also exhibit at least four of the five cardinal symptoms. This is particularly applicable if there are signs of redness or swelling of the palms or soles or if there is edema in the hands and feet [ 2 ].We term this the “4-4-4 rules” (coined by Prof. HC Kuo), encompassing the requirement for a minimum of 4 days of fever, the presence of more than 4 major criteria, and changes in 4 limbs. These diagnostic criteria have gained widespread acceptance in both research and clinical contexts. It is essential to recognize that the cardinal manifestations of KD might not all manifest concurrently and might even diminish before an accurate diagnosis can be established. Consequently, a comprehensive medical history and repeated assessments (conducted every other day) are crucial for the precise and prompt identification of KD.

Updated Diagnostic Criteria for Kawasaki Disease.

* and ** author’s comment for the criteria comparison.

Rapid memory of Kuo’s 1-2-3-4-5 mnemonic for Kawasaki disease.

Additional minor clinical symptoms that could be evident in KD patients but are not encompassed by the major diagnostic criteria consist of arthritis, gastrointestinal involvement (with a lower incidence compared to multisystem inflammatory syndrome in children, MIS-C), irritability, lethargy, neurological manifestations, cough, and rhinorrhea (with a lower incidence compared to MIS-C). Arthritis, primarily affecting the large joints of the lower extremities (such as the knees, hips, and ankles), can be identified in 7.5% to 25% of patients and is typically temporary and non-deforming [ 4 ].Arthritis following the acute phase of KD also suggests ongoing inflammation, prompting the consideration of anti-inflammatory treatment involving steroids for these children. In a study involving 198 KD patients, additional prodromal symptoms experienced during the acute phase of the disease encompassed irritability in 50% of patients, vomiting in 44%, diarrhea in 26%, and abdominal pain in 18% [ 5 ]. In exceptional instances, abdominal imaging techniques such as radiographs or computed tomography (CT) scans might reveal indications of pseudo-obstruction, a condition that can sometimes manifest prior to the appearance of cardinal symptoms [ 6 ]. KD should also be taken into consideration in the differential diagnosis of infants and children who exhibit a prolonged fever lasting over 7 days and unexplained aseptic meningitis. Among the 1582 KD patients reviewed, 80 (5.1%) displayed evidence of neurological engagement. Lethargy was the predominant symptom (50.1%), followed by irritability (26.3%), meningeal irritation (18.8%), convulsions (17.5%), headache (16.3%), bulging fontanelles (8.8%), and facial palsy (1.3%) [ 7 ]. Based on the summary derived from our compilation of 110 KD cases, the prevalent characteristics of the disease are represented by rashes, desquamation, conjunctivitis, and strawberry tongue (occurring in over 90% of cases); induration (75–80%); pyuria (50%); BCG induration (35–40%); neck lymphadenopathy (25–30%); diarrhea (21–25%); and arthritis (5–10%) [ 8 ]. The figure from our previous publication was included in the Nelson Textbook of Pediatrics, 20th edition, page 1210. The clinical symptom spectrum of KD is shown in Figure 1 below.

An external file that holds a picture, illustration, etc.
Object name is ijms-24-13948-g001.jpg

Percentage of clinical symptoms and signs of Kawasaki disease.

Yet another clinical manifestation of KD is Kawasaki disease shock syndrome (KDSS), which, while uncommon, is severe. It is characterized by shock, hypotension, compromised left ventricular systolic function, mitral regurgitation, consumptive coagulopathy, and a notable heightened risk of both CAL and a lack of response to intravenous immunoglobulin (IVIG) treatment [ 9 ]. Due to clinical resemblances, including symptoms such as rash, fever, and shock, patients afflicted with KDSS might be erroneously diagnosed as having toxic shock syndrome [ 10 ]. KD may also manifest as cervical lymphadenitis and exhibit contiguous cellulitis and phlegmon that mimic bacterial adenitis [ 11 ], especially in children less than 6 months old or more than 4–5 years old [ 12 ]. The potential for KD should be taken into account when evaluating infants and children (over 4–5 years old) who present with extended fever, cervical lymphadenitis, and retropharyngeal or parapharyngeal phlegmon, especially if they show poor response to antibiotic treatment [ 2 ].

In countries such as Taiwan, China, or Japan, where vaccination programs routinely administer the Bacillus Calmette-Guérin (BCG) vaccine, around 50% of KD patients may exhibit induration, erythema, or crusting around the BCG vaccination site. These symptoms can potentially assist in the diagnosis of KD, particularly among children under 3 years of age [ 8 , 13 ]. BCG site induration is a distinctive clinical symptom of KD, although it is not included in the five major criteria of either the AHA or Japanese guidelines. In a previous study involving 34 KD patients, the induration around the BCG vaccination site was categorized into three prevalent patterns: a targetoid bull’s eye pattern centered around the BCG site, uniform erythema surrounding the BCG site, or a whitish patch at the BCG inoculation site. Patients displaying a targetoid bull’s eye pattern around the BCG site during KD diagnosis were correlated with an elevated risk of coronary artery dilatation [ 14 ].For patients who have received the BCG vaccine and meet only four of the primary symptoms outlined in the Japanese guidelines, the presence of erythema, induration, or crusting around the BCG vaccination site could offer a significant indicator highly suggestive of a KD diagnosis. Erythema at the BCG vaccination site is relatively specific to a diagnosis of KD, although it has also been observed in connection with measles and human herpesvirus type 6 (HHV6) infections [ 15 ]. The existence of BCG infections in febrile children serves as a strong reason for clinicians to consider the potential of KD. The BCG vaccination reaction in KD is thought to involve a T-cell immune response. Uehara et al. reported and proposed that redness at the BCG vaccination site is a valuable indicator for diagnosing KD, particularly in nations with a BCG vaccination regimen. Even when patients display 4 or fewer of the 5 major clinical criteria for KD, doctors should be aware that individuals with BCG site reactions could potentially be dealing with KD [ 13 ].

3. The Importance of Induration over Peripheral Extremities in Kawasaki Disease

Our research team devised a wireless optical monitoring system that employed a tri-wavelength light source (700, 910, and 950 nm) along with a light detector to assess the extent of edema in the palm and sole tissues of febrile patients under suspicion for KD. In comparison to age-matched febrile controls, KD patients exhibited notably higher relative peripheral edema with increased water concentrations and decreased total hemoglobin concentrations. Subsequently, we documented alterations in tissue hemoglobin and water levels at varying stages of KD through near-infrared spectroscopy detection. Our findings demonstrated a significant correlation between water content and the development of CAL [ 16 ]. As a result, this non-invasive device could offer valuable assistance to physicians in promptly identifying KD and differentiating it from other fever-related conditions. We hold a positive outlook that wireless optical monitoring has the potential to furnish an extra non-invasive diagnostic tool, particularly for patients suspected of having KD but not meeting the conventional clinical criteria [ 17 ]. The presence of limb indurations and the elevation of water content detected through near-infrared spectroscopy over the palm region align well with the 2017 AHA 4-4-4 rule. This underscores the significance of indurations in the peripheral extremities as a diagnostic indicator for KD.

4. Diagnosis of Incomplete (or Atypical) Kawasaki Disease

Up to 10–15% of KD patients whose diagnosis is confirmed through an echocardiogram do not fulfill the criteria mentioned earlier. This subgroup of patients is often referred to as having “incomplete” or “atypical” KD [ 18 ], especially in infants younger than one year old [ 19 , 20 ] and children older than 5 years old. In 2004, the AHA introduced guidelines to assist in diagnosing incomplete KD, offering supplementary criteria. For patients with incomplete KD, the administration of high-dose IVIG (2 gm/kg) is recommended for those who meet all four of the following criteria: (1) fever lasting 5 days or more; (2) presence of two or three clinical KD symptoms; (3) elevated C-reactive protein (CRP) level exceeding 3.0 mg/dL or an erythrocyte sedimentation rate (ESR) surpassing 40 mm/h; and (4) fulfillment of at least three of the supplementary laboratory criteria (age-appropriate anemia, platelet count of ≥450,000/mm 3 after the 7th day of fever, albumin level ≤3.0 g/dL, elevated alanine transaminase, white blood cell count of ≥15,000/mm 3 , urine white blood cells ≥10/high-powered field) or a positive echocardiogram ( Table 3 ) [ 21 ]. Additionally, for patients exhibiting a fever lasting 5 or more days and two or three of the cardinal symptoms of KD, it is advisable to conduct sequential clinical and laboratory monitoring every other day in case the fever persists. Moreover, if there is periungual peeling of the fingers and toes, it is recommended to undergo supplementary echocardiography.

Echocardiography Findings in Kawasaki Disease.

Diagnosing KD can be more challenging in infants and older children above 5 years of age. Infants under 6 months old are more likely to exhibit incomplete KD, which can result in delayed IVIG therapy and an increased risk of coronary artery involvement. This risk persists even among those who receive IVIG therapy within 10 days of the disease’s onset [ 22 , 23 ]. In an analysis of 113 KD patients, those who were older than 5 years old exhibited cardinal KD symptoms later in the clinical progression. They were also inclined to display more pronounced signs of inflammation, characterized by elevated levels of erythrocyte sedimentation rate (ESR) and a prolonged duration of fever. This group was also at a heightened risk of being resistant to IVIG treatment. Intriguingly, older children were also more likely to experience cervical lymphadenopathy, and in some cases, their initial presentation occurred after the onset of fever. This pattern was in contrast to children under 5 years old, among whom the initial presentation often took place alongside fever (85.0% vs. 51.6%) [ 24 ].

Numerous viral infections, such as adenovirus, measles, and Epstein-Barr virus (EBV), exhibit clinical symptoms that resemble those of KD, such as fever, rash, and inflammation of the mucous membranes of the eyes and mouth [ 2 ]. Recognizing that KD can coincide with both bacterial and viral infections is essential, and it is important to note that confirming a bacterial or viral infection does not necessarily rule out the possibility of a KD diagnosis [ 25 , 26 ]. Lee et al. reported that the likelihood of IVIG resistance rises with higher CRP values and the utilization of multiple intravenous (IV) antibiotics. This suggests that physicians should exercise caution when administering multiple IV antibiotics to treat suspected infections in children with KD [ 27 ]. Administering antibiotics is unnecessary and not recommended as a standard treatment when diagnosing KD in the absence of evidence indicating a bacterial infection.

5. Echocardiographic Findings Aid to Make Precise Diagnosis of Kawasaki Disease

Echocardiography should be conducted for all individuals suspected of or confirmed to have KD. This practice is valuable not only for aiding KD diagnosis but also for establishing a baseline of echocardiographic parameters for future monitoring. The assessment should cover the visualization of all major segments of the coronary artery, including observations of diameter dilatation, irregular arterial wall, non-tapering, or increased echogenicity of the artery wall. Additionally, ventricular wall motion, ejection fraction, valvular regurgitation, fistula formation, and the presence of pericardial effusion should be monitored. It is strongly recommended to use a high-frequency transducer in both infants and older children to enhance coronary artery visualization [ 2 ]. CAL can reach their maximum diameter within four to six weeks after the onset of KD and may subsequently regress over a span of one to two years or even longer, depending on the size of the aneurysm. Consequently, having a normal echocardiogram during the initial week of disease onset does not rule out a diagnosis of KD. In cases where there is a strong suspicion of KD, it is advisable to undergo serial examinations every other day.

Measuring the internal diameter of coronary arteries is critical and can be categorized using absolute dimensions, as outlined in the Japanese JCS criteria [ 3 , 28 ] or be adjusted according to the patient’s body weight and body height of body surface area (AHA Guidelines) [ 2 ]. According to the Japanese guidelines, coronary arteries are considered dilated if the internal diameter exceeds 3 mm in a child younger than 5 years old or 4 mm in a child older than 5 years old. Coronary artery dilatations can be categorized as follows: ( Figure 2 ).

An external file that holds a picture, illustration, etc.
Object name is ijms-24-13948-g002.jpg

Coronary artery dilatations can be categorized as normal, small, medium and giant size (left to right). LCA: left coronary artery ( a ); LAD: left anterior descending artery ( b ); RCA: right coronary artery ( c ). (left upper white bar means 1 cm in scale in each figures).

Small aneurysm: 3 mm to 4 mm in children younger than 5 years old; >4 mm or if the internal diameter is less than 1.5 times that of an adjacent segment in children older than 5 years old.

Medium aneurysm: Internal diameter of 4 mm to 8 mm in children younger than 5 years old; 1.5 to 4 times the size of an adjacent segment in children older than 5 years old.

Giant aneurysm: Internal diameter exceeding 8 mm in children younger than 5 years old, or if it measures more than 4 times that of an adjacent segment in children older than 5 years old.

However, grading coronary artery size based solely on absolute measurements of diameter and age does not consider differences in body size or height, which can result in underestimating the extent of coronary artery involvement in up to 27% of patients [ 29 ]. Hence, significant endeavors have been directed towards standardizing coronary artery dimensions across various age and weight groups through body surface area (BSA) adjustments. The Z-score, which indicates the number of standard deviations from the mean values, has been adopted as the foundation for evaluating coronary artery diameters in line with the AHA guidelines. In this context,

Coronary artery diameters are considered normal if Z-scores are less than 2.

Dilation is indicated if Z-scores range from 2 to 2.5.

Small aneurysms are characterized by Z-scores of 2.5 to 5.

Medium aneurysms encompass a Z-score of 5 to 10, along with an absolute measurement of less than 8 mm.

Large or giant aneurysms correspond to a Z-score exceeding 10 or an absolute measurement surpassing 8 mm. Indeed, the Z-score offers a more accurate assessment of coronary artery dilation compared to the traditional method of measuring coronary artery diameter.

6. Novel Biomarkers to Assist in the Diagnosis of Kawasaki Disease

Numerous inflammatory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values, white blood cell (WBC) counts, and platelet counts, can contribute to the diagnosis of KD, either in combination with clinical symptoms or independently. However, these inflammatory markers are generally nonspecific to KD and can also become elevated in other conditions involving infection, inflammation, or autoimmunity. For instance, in a study involving 114 patients under suspicion of KD, an ESR level of ≥40 mm/h exhibited a sensitivity of 90.5% but a specificity of merely 66.6% [ 30 ]. Researchers at Stanford University have formulated two scoring systems aimed at distinguishing between KD and febrile controls. The initial scoring system, introduced in 2013, employed five clinical symptoms and 12 laboratory data points (a total of 17 parameters) to categorize febrile patients into low-risk (with a negative predictive value exceeding 95%), intermediate-risk, and high-risk (with a positive predictive value greater than 95%) KD groups [ 31 ]. Nevertheless, even after this stratification, a portion of febrile patients (approximately 20–30%) could not be classified. In response, a subsequent algorithm involving 18 clinical and laboratory data points were devised. This new algorithm employed data-mining models to re-stratify patients with the aim of enhancing the identification of KD among children presenting with fever [ 32 ] which was further confirmed by a Taiwanese cohort with 418 KD and 259 FC from Kaohsiung Chang Gung Memorial Hospital [ 33 ].

We endeavored to create a more streamlined scoring system that effectively distinguishes between patients with fever and those with KD. After analyzing 6310 febrile patients and 485 KD patients, we constructed a scoring system employing solely eight laboratory criteria. Notably, the highest scores were assigned to eosinophil percentage exceeding 1.5%, CRP exceeding 24 mg/L, and alanine aminotransferase level exceeding 30 U/L [ 34 ]. The present clinical symptoms of KD did not enroll in this algorithm to predict the possibility of KD.

Prior research has indicated that KD is linked to heightened expression of various T helper (Th)-1 cytokines, such as IL-6, IL-12, TNF-alpha, CXCL10 (also known as IFN-γ-inducible protein 10 [IP-10]), and IFN-gamma. Additionally, elevated levels of Th2 cytokines, including IL-4, IL-5, IL-13, and IL-31, have been associated with KD [ 35 , 36 , 37 ]. Both Th1 and Th2 immune responses exhibit elevation during the acute stage of KD. Notably, the Th2 immune response appears to exert certain anti-inflammatory effects.

B-type natriuretic peptide (BNP) and its inactive cleavage product, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), are investigated as proteomic biomarkers for KD. BNP is generated by ventricular cardiomyocytes as a response to ventricular stretching. It is recognized as a well-established biomarker for both congestive heart failure and coronary artery diseases [ 38 ]. The precision of NT-proBNP as a diagnostic biomarker for distinguishing KD from other febrile illnesses was recently assessed in a meta-analysis encompassing six studies involving a total of 279 KD patients. In this analysis, the biomarker demonstrated a combined sensitivity of 89% and a combined specificity of 72% [ 39 ]. Age-specific variations in NT-proBNP levels have been observed, with the highest levels occurring in the initial days after birth. These levels subsequently undergo a rapid decline during the first few weeks of life and continue to gradually decrease with age. These fluctuations make it challenging to establish a definitive cut-off value for NT-proBNP [ 40 ].

Escherichia coli ( E. coli ) proteome microarrays comprise approximately 4200 purified E. coli proteins and are utilized to examine the presence of anti- E. coli protein IgG and IgM antibodies in the patient’s serum samples. [ 41 ]. Contemporary theories of KD propose that the condition arises from an exaggerated immune response triggered by a common environmental or infectious factor. However, a universally acknowledged infectious trigger for KD has not yet been definitively identified [ 42 ]. Case reports have presented instances suggesting that E. coli and other Gram-negative pathogens, including Klebsiella oxytoca, could potentially serve as infectious triggers for KD [ 43 , 44 ]. Research focused on the gastrointestinal microbiota of KD patients has revealedincreased quantities of both Gram-positive and Gram-negative bacteria that produce heat shock proteins in the stool samples of individuals with KD [ 45 ]. E. coli is a prevalent bacterium in the gut and plays a role in the establishment of immune balance and the potential emergence of autoimmunity in young children [ 46 ]. Collectively, these investigations propose that E. coli might be a pertinent pathogen linked to the progression of KD. Pathogen-associated molecular patterns (PAMPs) and Toll-like receptors may also play a role in the context of KD. Our research revealed that individuals with KD exhibit distinct antibody profiles against E. coli , underscoring the significant role that E. coli potentially holds in the development of KD [ 47 ]. E. coli proteome microarrays have been previously documented in various diseases, including inflammatory bowel disease [ 48 ] and bipolar disorder [ 49 ]. Given that microarray testing using E. coli proteome microarrays necessitates only 125 picoliters of serum (equivalent to less than a single drop of blood), this method could potentially serve as an innovative approach for screening and aiding in the diagnosis of KD.

MicroRNAs (miRNAs) are short, non-coding RNA molecules comprising approximately 22 nucleotides. These molecules play a role in regulating gene expression by impeding the translation of mRNA into proteins. MiRNAs are present in various cell types, including erythrocytes, leukocytes, and platelets. Recent research indicates that miRNAs enclosed within exosomes can be detected in plasma, potentially engaging in gene regulation and mediating communication between distant cells [ 50 ]. A significant portion of the microRNAs detected in the serum of KD patients could potentially influence the growth and functionality of vascular endothelial cells. Among these microRNAs, miR-233 stands out as one of the most prominently expressed in the serum of individuals with KD [ 51 ]. Genes such as IGF1R and IL-6ST are among the targets for miR-233 [ 52 ]. MiR-233-3p directly targets the 3′ untranslated regions (UTR) of IL-6ST and effectively inhibits the expression of the crucial inflammatory cytokine IL-6 in KD. This inhibition consequently leads to a reduction in the expression of pivotal transcription factors such as p-STAT3 and NF-kB p65. In a KD mouse model, administration of miR-233-3p demonstrates a mitigation of vascular endothelial damage and the suppression of expression in key vascular adhesion molecules, including E-selectin and ICAM-1, as well as IL-6 [ 53 ].

Several other microRNAs have been documented to trigger apoptosis, such as miR-186 and miR-125-5p, or impede vascular cell proliferation, as observed with miR-27b. Notably, serum miR-186 has been identified as a promoter of endothelial cell apoptosis through the involvement of the SMAD6 and MAPK pathways [ 54 ]. Similarly, miR-125-5p has been observed to initiate endothelial cell apoptosis by engaging the MKK7 and Caspase-3 pathways [ 55 ]. The elevation of miR-27b in an endothelial cell line leads to the inhibition of the TGF-beta pathway and subsequent suppression of endothelial cell proliferation and migration, facilitated by SMAD7 [ 56 ]. Serum obtained from KD patients has exhibited decreased levels of miR-483. This microRNA is known to target the untranslated region of connective tissue growth factor (CTGF), a factor implicated in coronary artery remodeling and fibrosis. Suppressed miR-483 expression in endothelial cells has been associated with heightened CTGF expression [ 57 ].

MicroRNAs (miRNAs) have also been linked to prognostic outcomes in KD. In a study involving 102 KD patients and 18 healthy controls, it was observed that KD patients who were resistant to IVIG treatment displayed notably elevated levels of miR-200c and miR-371-5p [ 58 ]. The progression of CAL has also been correlated with the upregulation of certain microRNAs. These include miR-92a-3p, miR-let-7i-3p, miR-145-5p, and miR-320a [ 59 , 60 ]. The transfection of miR-145-5p and miR-320a into THP-1, a monocyte cell line, resulted in heightened expression of the inflammatory cytokines IL-6 and TNF-α. Moreover, immunohistochemical staining of a coronary artery sample obtained from KD patients exhibited escalated expression of miR-145-5p and miR-320a within the endothelial cells [ 61 ].

Identifying a single miRNA might not be as effective as determining a complete miRNA expression profile in distinguishing KD from fever controls. This is due to the likelihood that around 60% of protein-encoding genes are co-regulated by multiple miRNAs simultaneously [ 62 ]. In our research involving 50 KD patients, miRNAs extracted from peripheral leukocytes were subjected to next-generation sequencing (NGS), allowing us to identify a total of 10 miRNAs. This selection of 10 miRNAs was subsequently employed as a screening panel for diagnosing KD within the validation set. Notably, this panel demonstrated a sensitivity of 83.3% and a specificity of 92.5% [ 63 ] Furthermore, the expression levels of these miRNAs exhibited a strong correlation with the diagnostic indicators of KD. By amalgamating these miRNAs into a single KD miRNA signature utilizing the SVM (Support Vector Machine) model, the discriminatory ability was significantly enhanced, achieving a discrimination power of 0.882. This signature displayed a sensitivity of 74.6% and a specificity of 89.9% when evaluated across 665 cases (data not yet published). It is important to note that this miRNA panel has been patented in multiple regions, including China, Taiwan, Hong Kong, Japan, and the U.S., for the purpose of distinguishing KD from other febrile diseases.

7. Elevated of Eosinophil in KD

The higher expression of eosinophils, which can increase even more after IVIG treatment, has been associated with IVIG treatment responsiveness in Kawasaki disease (KD). This suggests a potential protective effect of eosinophils in KD. Interestingly, KD patients who exhibit lower Th2 immune responses (such as IL-5 or eosinophil levels) have been found to be at a higher risk of developing CAL. This implies that Th2 responses may play a protective role against the development of CAL in KD. This highlights the complexity of immune responses and their potential impact on the outcomes of KD [ 36 ]. Liu et al. [ 64 ] conducted a study involving 800 children, out of whom 249 were diagnosed with Kawasaki disease (KD) and 551 were age- and gender-matched children with non-KD febrile infectious diseases. In this study, both univariate and multivariate logistic regression analyses were employed, along with the development of nomogram models to analyze the experimental data. The children were divided into two groups:A total of 562 in the model group and 238 in the verification group.The prediction nomogram was constructed based on several factors, each assigned a certain point value: high eosinophil percentage (100 points), high C-reactive protein (CRP) levels (93 points), high alanine aminotransferase (ALT) levels (84 points), low albumin levels (79 points), and high white blood cell (WBC) count (64 points). The collective factors led to an area under the curve (AUC) of 0.873 for the model group and 0.905 for the validation group. Among all the parameters derived from routine laboratory data, eosinophils showed the highest odds ratio (OR) of 5.015 (95% CI: 3.068–8.197) during the multiple logistic regression analysis. In the validation group, the sensitivity was 84.1% and the specificity was 86%. This indicates that eosinophils play a crucial role in the nomogram model as the most significant predictor of KD.

Tsai et al. [ 34 ] conducted a comprehensive analysis involving 6310 febrile children and 485 subjects diagnosed with Kawasaki disease (KD). The study focused on evaluating routine blood test parameters, which included complete blood count with differential (CBC/DC), C-reactive protein (CRP), aspartate aminotransferase, and alanine aminotransferase. They utilized various statistical tools such as the receiver operating characteristic curve, Youden’s index, and logistic regression model to construct a prediction model. The research identified eight independent predictors that could differentiate between KD and other febrile illnesses. Among these predictors, eosinophils >1.5% had the highest score [ 7 ], followed by alanine aminotransferase >30 U/L [ 6 ] and CRP >25 mg/L [ 6 ]. A total score of 14 (from a maximum of 30) yielded the best prediction rate, combining sensitivity and specificity for KD. The calculated sensitivity, specificity, and accuracy values were 0.824, 0.839, and 0.838, respectively. Verification tests were carried out on two independent cohorts from different hospitals (Kaohsiung, Taiwan, and Shenzhen, China), comprising 273 subjects. The validation showed a sensitivity of 0.780 (213/273) for accurately identifying KD cases. Remarkably, this study exclusively utilized routine laboratory data from CBC/DC, CRP, and liver enzyme levels (GOT/GPT) without considering factors such as age, gender, clinical symptoms, or urine findings. The study highlighted the pivotal role of eosinophils in distinguishing KD from other febrile illnesses, suggesting the potential inclusion of eosinophils as an independent factor in the supplementary diagnostic criteria for KD, as outlined by the AHA.

8. Consulting a Clinical Expert on Kawasaki Disease

When dealing with children who exhibit prolonged fever exceeding 7 days without a clear diagnosis, seeking consultation from a team of Kawasaki disease (KD) specialists is essential. This specialized team would ideally include experts from various fields, such as immunology, rheumatology, cardiology, infectious diseases, and KD clinical expertise. Collaborating with a multidisciplinary team ensures accurate diagnosis and timely treatment to prevent the development of CAL. The diagnostic process for KD, which relies on five key clinical symptoms, can introduce subjectivity. Involving a clinical expert in KD can enhance the accuracy and objectivity of the diagnosis. Consulting experts who possess vast experience and knowledge in the field of KD increases the likelihood of an accurate assessment. To assist in identifying qualified KD experts, the expertscape directory provides a valuable resource. This directory offers objective rankings of medical expertise and can be searched based on various criteria such as city, region, country, and continent. It is important to prioritize clinical experts who specialize in KD over research experts, as clinical expertise is particularly relevant for accurate diagnosis and patient care.

9. IVIG Resistance (IVIG Non-Responsiveness or IVIG Failure) in Kawasaki Disease

KD patients with IVIG resistance have a higher risk of developing CAL. Identifying high-risk patients who may benefit from more aggressive treatment is important. Administering a second dose of IVIG (2 g/kg over 10–12 h, following the same dosage and treatment duration as the initial IVIG) is a consideration [ 65 , 66 ] methylprednisolone pulse therapy [ 67 ] tumor necrosis factor-alpha blockade [ 68 ] cyclophosphamide; cyclosporine A; plasmapheresis [ 69 ] methotrexate [ 70 ] and plasma exchange [ 71 ] have all been reported to be beneficial for KD patients with initial IVIG-resistance. IVIG is recognized as the primary standard treatment for KD in accordance with AHA and Japanese guidelines. However, there is currently no established standard treatment for KD cases resistant to IVIG. The utilization of single-pulse intravenous methylprednisolone (IVMP), with a dose of 30 mg/kg (up to a maximum of 1000 mg), in conjunction with initial IVIG has not demonstrated a significant improvement in the disease’s outcome for children with KD [ 72 ]. While the addition of IVMP to IVIG for initial treatment does not appear to enhance therapeutic efficacy, the underlying mechanism for this remains unclear. However, it is worth noting that administering IVMP therapy over a span of three days does seem to offer benefits for patients with IVIG-resistant KD [ 66 ]. Steroid receptor expression changes following IVIG treatment in KD could potentially shed light on the role of IVMP pulse therapy after IVIG, although not in combination with IVIG for KD. At Kaohsiung Chang Gung Memorial Hospital in Taiwan, we adopted a two-step approach for managing IVIG-resistant KD cases. Initially, a second course of high-dose IVIG (2 g/kg over 10–12h) was administered for patients who showed resistance to the initial IVIG treatment. For those who continued to be resistant to IVIG, a secondary dose of IVMP (30 mg/kg/day for 3 days) was prescribed. In instances of ongoing resistance even after IVMP, an anti-TNF-alpha agent such as infliximab (5 mg/kg) was utilized.

10. Potential Role of Molecular Hydrogen Gas (H 2 ) in Kawasaki Disease

Oxidative stress, inflammation, and the generation of free radicals are all interconnected processes that play a significant role in the pathogenesis of KD and the formation of CAL [ 73 ]. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them through antioxidants [ 74 ]. In KD, the immune response and inflammation triggered by an infectious or environmental trigger can lead to the production of ROS and oxidative stress. This oxidative stress can damage cellular components, including lipids, proteins, and DNA. The endothelial cells lining the coronary arteries are particularly susceptible to oxidative damage, which can contribute to inflammation, vasculitis, and ultimately the development of CAL. Oxidative stress also promotes the release of pro-inflammatory cytokines and chemokines, amplifying the immune response and contributing to tissue damage. The resulting inflammation and tissue injury further exacerbate oxidative stress, creating a cycle that can lead to the progression of KD and the formation of CAL. It has been reported that molecular hydrogen gas (H 2 ) exhibits beneficial effects in a variety of diseases by reducing oxidative stress. These diseases include rheumatoid arthritis (RA), atopic dermatitis (AD), hay fever, asthma, chronic obstructive pulmonary disease (COPD), COVID-19, severe COVID-19, stroke, depression, dementia, post-cardiac arrest syndrome, subarachnoid hemorrhage, myocardial infarction, chronic kidney disease, sepsis, hemorrhagic shock, and various cancers [ 75 , 76 ]. Hydrogen gas inhalation was reported to have a role in the treatment of COVID-19, reducing disease progression by improving airway resistance and inflammation [ 76 ]. Furthermore, a preliminary investigation has reported that inhaling hydrogen gas can lead to a significant improvement in breathing difficulties for the majority of COVID-19 patients. [ 77 ]. We conducted the initial study on a KD-related aneurysm (measuring 6.08 mm in diameter and 35 mm in length) that exhibited regression (complete regression at the 4-month follow-up, on day 138 of the illness) with the addition of supplementary therapy involving hydrogen gas inhalation, and no other complications were observed. Hydrogen gas inhalation could potentially serve as an alternative therapy for KD by acting as an antioxidant or anti-free radical agent, although further research is still necessary [ 78 ]. Cardiovascular diseases such as post-cardiac arrest syndrome, subarachnoid hemorrhage, and myocardial infarction are also associated with oxidative stress and inflammation. Hydrogen’s antioxidant and anti-inflammatory effects might contribute to cardiovascular protection and the possibility of treatment effects for KD, MIS-C, or COVID-19;however, we still need more clinical studies. The potential therapeutic impact of hydrogen gas inhalation in patients with KD, whether with or without CAL formation, also demands further investigation. Additionally, COVID-19 has been associated with the emergence of a KD-like condition known as multisystem inflammatory syndrome in children (MIS-C), representing a novel syndrome linked to SARS-CoV-2 infection in pediatric populations [ 79 , 80 , 81 ]. The comparison between KD and multisystem inflammatory syndrome in children (MIS-C) is shown in Table 4 .

Comparison between Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C).

This table was modified and adapted from Chen et al. [ 73 ].

11. Conclusions

The Kuo mnemonic, 4-4-4 rule, BCG vaccination induration, AHA supplementary criteria, and strategic echocardiography scheduling collectively contribute to the prompt diagnosis of KD and the prevention of CAL formation. Biomarkers such as eosinophil count, miRNA expression, inflammatory cytokines, and E. coli antibody profiles have demonstrated significance in differentiating KD from other febrile conditions. Seeking advice from KD specialists, appropriate and intensified interventions for IVIG resistance, and adjunctive therapies such as hydrogen gas inhalation can further enhance the therapeutic outcomes for KD.

Funding Statement

This work was also supported by Chang Gung Memorial Hospital (CORPG8N0071, CLRPD1J0012, CMRPG8M1421, CMRPG8M1431,CMRPG8L1241-2, CMRPG8M1261-2)and the Ministry of Science and Technology of Taiwan (NSTC 111-2314-B-182-063, NSC- 112-2314-B-182-032-MY3).

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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A, Total KD patients for Kawasaki Disease Comparative Effectiveness Trial (KIDCARE) sites: 2018, 894 cases; 2019, 905 cases; 2020, 646 cases. There was a 27.7%-28.6% reduction in case numbers in 2020 compared with previous years. B, Incidence of KD by month of year at Rady Children’s Hospital San Diego during 2002 to 2019. Light blue line is the mean for 2002 to 2019, with errors bars indicating 2 SDs. Cases rebounded to close to within historic levels in late 2021.

A-D, Error bars show the 5th to 95th percentile confidence interval for annual patient counts from 2002 to 2019. B-D, The largest reductions in cases in 2020 were in male children younger than 5 years and among Asian children. In 2021, cases among female and White children also decreased. E-G, Black dots show annual values for 2002 to 2019, with boxes indicating the IQR, the bar indicating the median, and whiskers indicating 1.5 × IQR, for those values. Several clinical features of KD were lower than average in 2020 compared with annual rates in previous years, and strawberry tongue and periungual desquamation remained low through 2021.

a P  < .05.

b P  < .01.

c P  < .10.

A, Patterns of mobility for Southern California were defined as the fraction of the day spent away from home and Kawasaki disease (KD) incidence, 2019 to 2021. Red and blue curves and shading show the median and IQR for the fraction of the day spent away from home for each day in census block groups that had (red) or did not have (blue) KD cases during that year. Tan lines show dates of onset of fever for each KD case at Rady Children’s Hospital San Diego. Black dashed lines show the 2020 pandemic-related shutdown and are included in 2019 and 2021 for comparison. B and C, Changes in tropospheric no 2 levels relative to the same period in 2019 for CBGs that had or did not have KD cases during that year and pandemic time period. Boxes indicate the IQR; bar, median; and whiskers, 1.5 × IQR. In 2020, during the shutdown period (March 3 to May 31), CBGs with KD cases had significantly smaller reductions in pollution (ie, neighborhoods where the no 2 levels were more similar to prepandemic levels were more likely to have KD cases during that period).

Respiratory viruses were detected by polymerase chain reaction in children tested at Rady Children’s Hospital San Diego from July 1, 2018, through November 30, 2021. The initial shelter-in-place period for San Diego County is shown in gray.

eTable 1. Participating Sites and Number of KD Cases (2018-2020) Grouped by Region

eTable 2. Summary of Missing Data From RCHSD Data Set

eTable 3. RCHSD Patients by Year and Pandemic-Defined Time Period

eTable 4. Demographic and Clinical Characteristics of Patients With KD at RCHSD, by Time Period

eFigure 1. KD Across 28 KIDCARE Sites Grouped by Region

eFigure 2. KD Incidence in 2020-2021 in San Diego (Patients per Month) Compared With 2002-2019 Baseline, Total and by Age Group

eFigure 3. KD Incidence in 2020-2021 in San Diego (Patients per Month) Compared With 2002-2019 Baseline, Fraction of Male Patients

eFigure 4. KD Incidence in 2020-2021 in San Diego (Patients per Month) Compared With 2002-2019 Baseline, by Race and Ethnicity

eFigure 5. Trends in Age of Patients With KD at RCHSD, 2002-2021

eFigure 6. Distribution of Laboratory Values for Patients With KD Seen at RCHSD

eFigure 7. Mobility Patterns Around COVID-19 Pandemic Onset in Southern California

eFigure 8. KD, Income, and Mobility by Year

eFigure 9. Laboratory Values for Patients With KD by Pandemic-Defined Season

eFigure 10. Clinical Presentation of Patients With KD in 2020 and 2021, Compared With 2002-2019 Baseline, by Pandemic-Defined Season

eFigure 11. Geographic Distribution of Patients With KD in RCHSD Data Set, 2019-2021

eFigure 12. Association Between Census Block Group–Level Median Household Income and Average Time Spent Away From Home

eFigure 13. KD Fever Onset by Day of Week

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Burney JA , Roberts SC , DeHaan LL, et al. Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States. JAMA Netw Open. 2022;5(6):e2217436. doi:10.1001/jamanetworkopen.2022.17436

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Epidemiological and Clinical Features of Kawasaki Disease During the COVID-19 Pandemic in the United States

  • 1 School of Global Policy & Strategy, University of California, San Diego, La Jolla
  • 2 Department of Pediatrics, University of California, San Diego, La Jolla
  • 3 Rady Children’s Hospital San Diego, La Jolla, California
  • 4 Scripps Institution of Oceanography, University of California, San Diego, La Jolla
  • 5 Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts
  • 6 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
  • 7 Department of Pediatrics, Pediatric Cardiology, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora
  • 8 Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, Georgia
  • 9 Division of Pediatric Cardiology, Children’s Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles
  • 10 Ann & Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 11 UAB Heersink, School of Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham

Question   How did the incidence and nature of Kawasaki disease (KD) in the United States change during the COVID-19 pandemic?

Findings   In this cohort study of 3922 children with KD, cases of KD across the United States fell by 28% and remained low during periods of COVID-19–related masking and school closure. In the San Diego region, there was a disproportionate decline in KD cases in children aged 1 to 5 years, male children, and Asian children, and clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were rare.

Meaning   These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

Importance   Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology.

Objectives   To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD.

Design, Setting, and Participants   This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children’s Hospital San Diego [RCHSD]).

Main Outcomes and Measures   For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence.

Results   A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P  = .02), male children (21 vs 47.6 [10.0]; P  = .01), and Asian children (4 vs 11.8 [4.4]; P  = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P  = .04; enlarged lymph node: 21% vs 32%; P  = .09; periungual desquamation: 47% vs 58%; P  = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates.

Conclusions and Relevance   In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).

The COVID-19 pandemic brought Kawasaki disease (KD) into the spotlight in 2 ways, one obvious and one more hidden. The sudden emergence of multisystem inflammatory syndrome in children (MIS-C), a rare but severe condition affecting children 2 to 6 weeks after infection with SARS-CoV-2, was initially confused with KD. Both conditions share an acute innate immune response with high levels of markers of inflammation and shared mucocutaneous signs. 1 As cases first appeared, KD clinicians were at the forefront of diagnosing MIS-C, delineating its differences from KD, and extrapolating KD knowledge and therapies to this new disease. MIS-C revealed a new illness paradigm, whereby exposure to SARS-CoV-2 was associated with a systemic inflammatory illness several weeks later. The other way in which KD was highlighted by the pandemic was by the reduction in KD case numbers. Recent reports from around the world have revealed significant reductions in KD incidence during 2020. 2 - 8

In this study, we combine analysis of 2 sets of information on KD incidence in the United States before and during the pandemic. In the United States, a multicenter clinical trial for KD (Kawasaki Disease Comparative Effectiveness [KIDCARE] trial; NCT03065244 ) allowed the prospective collection of date of onset of KD cases across the 28 participating clinical centers from 2018 through 2020. 9 Additionally, more detailed analyses of population behaviors as well as demographic and clinical details of KD cases were performed at a single pediatric referral center in San Diego using data from time periods before, during, and after the height of the pandemic, from January 2002 to November 2021.

All patients who met the American Heart Association (AHA) definition for complete or incomplete KD from January 1, 2018, through December 31, 2020, were included in this analysis. Date of onset was defined as the first day of fever and was reported monthly for all patients from 28 institutions participating in the KIDCARE trial. 9 The institutional review board (IRB) at the University of California, San Diego (UCSD; central IRB for trial) and participating sites approved the study. A waiver of informed consent was granted for collection of dates of KD onset because they are not protected health information.

Data from the KD Research Center at Rady Children’s Hospital San Diego (RCHSD)/UCSD in San Diego included 1461 patients meeting the strict AHA case definition for complete and incomplete KD, with the exception of 46 individuals (3.3%) from January 1, 2002, to February 28, 2020, and 3 individuals (4.6%) from March 1, 2020, to November 15, 2021. Historically, 95% of all KD cases hospitalized in the San Diego region receive care at RCHSD. One of 2 dedicated KD physicians (J.C.B. and A.H.T.) evaluated each patient during the acute phase and again as outpatients 7 to 21 days after discharge. Prospectively collected data included age at onset, self-reported race and ethnicity (Asian, Black, Hispanic, Indigenous, multiracial, Pacific Islander, unknown, White, and other [including Middle Eastern, North African, and South Asian]), global positioning system coordinates for the patient’s home, and details of the clinical and laboratory evaluation at presentation and over time. The IRB at UCSD approved the study, and parents and participants signed informed consent and assent forms as appropriate. We followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for cohort studies. 10

Analysis of human movement patterns (hereafter, mobility analysis) used information about the timing of public health orders and publicly available, anonymized mobile phone data provided by Safegraph. Safegraph data were used to show the median time spent away from home by residents of all of the census block groups (CBGs) in the 3 counties constituting southern California from January 2019 to April 2021. These data quantified the practice of sheltering in place in different locations and different phases of the COVID-19 pandemic. We used data from the American Community Survey (ACS) on median household income by CBG to relate mobility and KD incidence to neighborhood socioeconomic status. Data were accessed using the TidyCensus package for R version 4.0.4 (R Project for Statistical Computing). For the San Diego time series, we linked Safegraph mobility data by CBG to the CBG where the patient lived at the time of KD onset. This allowed assessment of whether KD cases were from neighborhoods that were sheltering in place more or less intensively.

Using Google Earth Engine, we aggregated and downloaded tropospheric column nitrogen dioxide ( no 2 ) data from the Troposhperic Monitoring Instrument (TROPOMI) on the European Space Agency’s Copernicus Sentinel-5 precursor satellite and found the mean over each CBG at a weekly time scale from January 2019 to October 2021. We merged no 2 data with the ACS and RCHSD KD data as described previously.

Data for polymerase chain reaction detection of common viruses by the GenMarkDX ePlex system was provided by the clinical laboratory at RCHSD.

For all patient counts, we tallied counts by year and compared the 2020 and 2021 values with the distribution of values from the 2002-to-2019 base period (for RCHSD data). For each value, we calculated a t statistic as follows: the 2020 or 2021 value minus the mean from 2002 to 2019, divided by the SD from 2002 to 2019. We then calculated the P value for this t statistic with 18 degrees of freedom. For clinical values, we did not use annual values but rather grouped all patients by time period (ie, 2002-2019, 2020, and 2021) and tested for a difference of medians using Kruskal-Wallis tests. For fractional values (eg, fraction of patients with strawberry tongue), we assessed statistical differences in 2 ways. In some instances, we present the value in 2020 or 2021 with the distribution of annual fractions from 2002 to 2019 for comparison; however, to assess statistical significance, we pooled all values from 2002 to 2019 and used the Fisher exact test to compare proportions from that time period with both 2020 and 2021 (eTable 4 in Supplement 1 ). For all tests, a 2-tailed P  ≤ .05 was considered statistically significant.

Although the pandemic-related public health orders did not begin until late February and early March 2020, we analyzed data for 2020 and 2021 as entire years because KD has a strong seasonal component that differs by age group. However, to probe dynamics more fully, we conducted additional exploratory subannual analysis (comparing pandemic-defined periods in 2020 and 2021 with the same seasonal values in the baseline 2002-2019 group). For these analyses, we compared the base period values (mean cases per month ±2 SD) with the 2020 and 2021 values. Because these were small statistics, we report qualitatively when 2020 and/or 2021 values were outside the 95% CI of the baseline period. Statistical differences in mobility and pollution data were also assessed using t tests by group and time period.

For Safegraph data, we used t tests to evaluate whether there were statistically significant differences in time spent away from home for CBGs that had (or did not have) KD cases in different time periods. A 2-tailed P   ≤ .05 was considered statistically significant. Analyses were conducted in R version 4.0.4 (R Project for Statistical Computing).

Nationally, we studied 2461 patients diagnosed with KD from 2018 to 2020. Across the multicenter study in the United States, the number of KD cases declined in 2020 ( Figure 1 A), with regional differences in the timing of the reduction in incidence (eTable 1 and eFigure 1 in Supplement 1 ). Overall, there was a 28.2% reduction in KD cases across these US sites in 2020 (646 cases in 2020 compared with 894 and 905 cases in 2018 and 2019, respectively). This decrease in case numbers was not spatially or temporally homogeneous. Lower case numbers in the winter and spring months of 2020 were driven by western states (Washington and California, excluding San Diego); summertime declines were driven by the Mountain West and Plains, Southeast, and San Diego; and autumn declines were driven by the Midwest and Northeast, with continued lower levels in California and Washington, San Diego, and the Southeast region (eFigure 1 in Supplement 1 ).

We studied 1461 patients (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) with KD who were diagnosed at RCHSD between January 1, 2002, and December 31, 2021 ( Table ; eTable 2 in Supplement 1 ). In the San Diego region, the 2020 to 2021 decline in case numbers was statistically significant compared with the base period ( Figure 1 B and Figure 2 A; eTable 3 in Supplement 1 ). In 2020, there was a 44% reduction compared with the mean (SD) number of cases in the baseline period (43 vs 76.8 [15.6]; P  = .02), and for 2021, there was a 53% reduction (36 vs 76.8 [15.6]; P  = .009). However, this unfolded unevenly for different subsets of patients. The 2020 decline was associated with a reduction in KD compared with the mean (SD) number of cases in the base period for children aged 1 to 5 years (22 vs 44.9 [9.9]; P  = .02), male children (21 vs 47.6 [10.0]; P  = .01), and Asian children (4 vs 11.8 [4.4]; P  = .046). ( Figure 2 B-D; eTable 4 and eFigures 2-4 in Supplement 1 ). Although we observed increasing patient age during the 2002-2021 period in the San Diego time series (eFigure 5 in Supplement 1 ), the older age of patients with KD in 2020 was primarily because of the disproportionate reduction in the number of younger patients with KD ( Figure 2 B). It should be noted that the timing of the pandemic occurred during the season that could conflate age effects with normal seasonal patterns, which differ slightly by age (eFigure 2 in Supplement 1 ). Rates of KD for patients younger than 1 year decreased initially but then rebounded ( Figure 2 B).

Clinical subphenotypes of KD in San Diego have been described, and we sought to determine whether there was a shift in the clinical and laboratory patterns of KD during the pandemic compared with previous years 11 ( Figure 2 E-G; eFigure 6 in Supplement 1 ). Although some variability in clinical characteristics was noted across the different time periods, the most notable difference was a reduction in patients with any or all of an enlarged cervical lymph node and strawberry tongue at the time of diagnosis as well as periungual desquamation in the subacute phase during 2020 ( Figure 2 E-G). Prior to the pandemic, approximately two-thirds of patients with KD had strawberry tongue, and two-thirds had periungual desquamation noted 2 to 3 weeks after fever onset (the notable exception in Figure 2 G is the data point from 2019); these features were markedly reduced during the lockdown of 2020 (strawberry tongue: 39% vs 63%; P  = .04; periungual desquamation: 47% vs 58%; P  = .16; and enlarged lymph node: 21% vs 32%; P  = .09) as well as for much of 2021. eFigure 10 in Supplement 1 presents subannual timing. The proportions of all 3 clinical features rebounded in 2021 to greater than prepandemic levels, although the differences were not significant because of the small numbers of patients. There was less variability in laboratory measures of inflammation during the pandemic, with no statistically significant changes observed (eFigure 6 in Supplement 1 ). Finally, although we observed a small reduction in average coronary artery z score for patients through 2021, the fraction of patients with aneurysms did not change.

The pandemic afforded a unique opportunity to examine the combined association of behavioral interventions with the likelihood of exposure to a KD trigger. While compliance with many of these measures was difficult to assess, average neighborhood movement away from home—a proxy for the intensity of sheltering in place—was possible through analysis of cell phone data aggregated by CBG. These data revealed that, on average, across southern California, residents dramatically reduced their movement starting around March 5, 2020 (shutdown vs before shutdown: P  < .001). Time away from home increased back to steady state but at levels lower than the prepandemic period after approximately June 1, 2020 (eFigure 7 in Supplement 1 ). Although the differences were small and not statistically significant both before and during the pandemic, the mean time spent away from home for CBGs with KD cases was slightly lower compared with CBGs with no KD cases ( Figure 3 A; eFigure 8 in Supplement 1 ).

We used the mobility patterns in 2020 and public health orders to define relevant pandemic periods ( Figure 3 A). This enabled comparison of 2020 and 2021 to prior years while accounting for both the known seasonality of KD and the very different public health environments over the course of the pandemic. We defined January 1 to March 5 as the prepandemic period in 2020. Although the state of emergency was declared in late February and the statewide shelter-in-place order was issued on March 19, the mobility data showed that behavior changed between those 2 dates as public awareness about COVID-19 grew. We similarly defined March 5 to June 1 as the shutdown period of 2020. This was again informed by the mobility data, as reopening of nonessential businesses began in early June, and the statewide mask mandate was issued June 18, 2020. Vaccinations began for health care workers and older individuals in late December 2020. By April 1, 2021, all adults were eligible for vaccines, and on May 5, 2021, statewide guidance declared that masks were no longer required for fully vaccinated individuals.

Although exploratory because of the small numbers of patients, more detailed analysis of KD incidence (ie, mean number of cases per month) over these pandemic periods revealed intriguing preliminary associations. Overall, KD incidence in San Diego decreased after the initial shutdown and stayed less than the 95th percentile of historical (ie, 2002-2019) levels until summer 2021 (eFigure 2 in Supplement 1 ). School-aged children (ie, >5 years) followed the same pattern, while younger children (1-5 years) had earlier reductions in incidence during the shutdown period (eFigure 2 in Supplement 1 ). The fraction of male children with KD also decreased during the initial shutdown period but recovered in spring 2021 (eFigure 3 in Supplement 1 ).

Patient clinical data at this finer temporal scale revealed no changes in laboratory values by pandemic-defined season (eFigure 9 in Supplement 1 ). However, the fraction of patients with strawberry tongue fell below the historical 95% CI during the pandemic period in 2020 and stayed outside the historical IQR through 2021. The fraction of patients with enlarged cervical lymph nodes followed a similar, although less extreme, pattern, staying low between the shutdown period in 2020 and spring 2021. The fraction of patients with periungual desquamation in the subacute phase fell during the immediate shutdown period and stayed less than average or outside the historical 95% CI until the second half of 2021 (eFigure 10 in Supplement 1 ). Although the appearance of these characteristics was reduced, we note that some anomalously low outlier years exist in the historical record (ie, black dots in eFigure 10 in Supplement 1 ).

For the San Diego region, exploratory analysis also revealed that the geographic location of KD cases shifted during the pandemic compared with previous years, with a concentration of cases along the northern coast of San Diego County (eFigure 11 in Supplement 1 ). We analyzed the spatiotemporal distribution of KD during the pandemic and its association with socioeconomic status (SES) of the CBG of the patient’s primary residence. In 2019, there was no statistical difference in SES between neighborhoods with and without KD cases. The spatial distribution of KD cases shifted during the pandemic, and KD cases were more likely to occur in neighborhoods with higher SES (median household income of CBGs with vs without KD cases, $90 916 vs $79 250; P  = .04) (eFigure 8 in Supplement 1 ). CBG mobility metrics were strongly associated with SES, with residents of wealthier neighborhoods spending more time at home at baseline (slope, −7.6 × 10 −6 ; P  < .001) and reduced time away from home during the initial shelter-in-place period (slope, −1.0 × 10 −6 ; P  < .001). This association was weaker during the rest of the pandemic, with the slope for the second half of 2020 only 29% of the slope during the shutdown period ( P  < .001) (eFigure 12 in Supplement 1 ).

At an even finer temporal scale, analysis of the day of the week for KD onsets was conducted to determine whether there were hebdomadal patterns, such as a weekend effect, that might suggest exposures associated with triggering the disease. In both the San Diego and national KIDCARE data, there was a small deviation from historical incidence patterns, with one-third of pandemic KD onsets in San Diego occurring on Fridays and higher numbers in both data sets on Wednesdays than in prior years (eFigure 13 in Supplement 1 ). However, in general, the breakdown of weekday vs weekend onsets remained constant. Day-of-week analysis thus suggested that there was not a weekend effect and complements the lack of a mobility association.

To understand more about the environmental changes and exposures, we examined both pollution levels and virus circulation preceding and during the pandemic. Previous work has shown that emissions of both greenhouse gasses and air pollutants, particularly from nonstationary sources (transportation) were significantly reduced during the initial shutdown period. 12 This resulted in lower exposures to both aerosol particulate matter and nitrogen oxides across much of the region during the spring of 2020 13 ; it has been further documented that these reductions were greater for lower-income neighborhoods and neighborhoods with higher proportions of Asian and Hispanic residents. 14 We examined satellite-derived near-surface concentrations of no 2 (a proxy for all oxides of nitrogen) by CBG over the study period. We found that no 2 levels for CBGs with KD cases during the shutdown period were reduced relative to the same time in 2019 but to a lesser extent than CBGs without KD cases ( Figure 3 B). That is, CBGs where pollution levels remained more similar to prepandemic levels were more likely to have cases in the spring of 2020 (reduction in no 2 levels of CBGs with vs without KD cases, −12.6% vs −21.4%; P  = .003 during the initial lockdown). Along with mobility, pollution levels rebounded to prepandemic levels by summer 2020, and no statistical difference in change relative to baseline persisted.

In addition to probing how human movement might have changed exposures to the agent(s) that trigger KD, we also conducted an exploratory examination of the prevalence of circulating viruses. Data were available for respiratory virus test results in children seen at RCHSD, a tertiary care facility that serves a population base of approximately 4 million people. The typical seasonal spike in respiratory viruses during the winter months was seen in 2018 to 2019 and 2019 to 2020 ( Figure 4 ). However, respiratory virus infections in children essentially disappeared during the winter of 2020 to 2021. There were no cold coronavirus cases from July through October 2020, and fewer than 1 case per week in November and December as well as April through June. The incidence of other respiratory viruses fell to zero in May and June of 2020, with less than 1 case per week in July and August. The prevalence of rhinovirus/enterovirus infection was less affected compared with other viruses, with a minimum incidence of approximately 1 case per week occurring in June through August of 2020. KD case numbers were reduced but not nearly as much as some respiratory viruses during the shelter-in-place period.

Our goal was to track national temporal trends in KD cases before and during the COVID-19 pandemic and to analyze in depth the association of pandemic-related behavior and environmental changes with KD incidence in the San Diego region. The reduction in KD case numbers coincided with masking, school closures, reduced circulation of respiratory viruses, and reduced air pollution. 13 A rebound in KD case numbers to prepandemic levels coincided with the lifting of mask mandates and, subsequently, the return to in-person schooling. Although similar reductions in KD cases have been reported in Chicago, Illinois; Asia; and Finland in 2020, the rebound of KD cases in 2021 has not yet been documented from other regions. 2 - 4 , 6 , 7 , 15 One concern was that the reduction in KD cases could have been related to parental fears about accessing care and the possibility of COVID-19 exposure in health care settings. 16 However, the report by Ae and colleagues 4 from Japan showed that the interval between fever onset and diagnosis was unchanged during the pandemic, suggesting that there was no delay in seeking medical attention.

Compared with prepandemic disease patterns in San Diego, the reductions in KD disproportionately occurred in male children, Asian children, and children aged 1 to 5 years. There was no change in the number of infants diagnosed with KD during the pandemic compared with the prepandemic period. This observation was echoed by a report from Japan. 4 Possible explanations include the fact that infants would not be subjected to pandemic-era behavior changes, such as masking, and changes in exposure to the KD trigger within the home, so decreased mobility would have little effect on KD incidence in this group.

Although our original hypothesis was that shelter-in-place measures would track with reduced KD cases, this was not borne out by the San Diego region data. Instead, the San Diego case occurrence data suggest that exposures that triggered KD were more likely to occur in the home, with a shift toward households with higher SES during the pandemic. The change in mobility by CBG did not account for the decreases in KD case numbers. Thus, the mobility data do not suggest an exposure mechanism associated with an inability to shelter in place as a consequence of employment or socioeconomic pressures. Sheltering in place may have had less impact on KD than other respiratory viruses if the triggering agent(s) are indeed airborne particles. Recent work has documented the relatively weak filtering provided by buildings: high air exchange rates, especially during the day, mean that changes in outdoor aerosol particulate matter are also observed indoors over short time periods. 17

The reduction in respiratory viruses during the pandemic has been documented from many sites. 2 , 18 - 20 The respiratory virus data reported here were uniquely from pediatric patients evaluated in a health care system serving a large catchment area in the San Diego region. Although the majority of respiratory viruses, including the cold coronaviruses essentially disappeared, rhinoviruses/enteroviruses rebounded following the shelter-in-place order, albeit at lower levels compared with prepandemic conditions. Although Hara and colleagues 2 argued that the disappearance of respiratory viruses argued against their role as a trigger for KD, the rapid rebound of the rhinoviruses/enteroviruses suggests that caution should be exercised in reaching such a conclusion, although no known respiratory virus has been implicated as a KD causative agent. The available data indicates that the trigger(s) for KD enter through the upper respiratory tract. 21 The role of other aerosols, including pollutants and microbial aerosols, in the etiology of KD remains an open question. Pollution, largely from the transportation sector, decreased during the pandemic in the Southern California region, 13 , 14 and the contribution that reactive oxygen species from these pollutants might play in the genesis of KD is unknown, although researchers in Canada have postulated a role. 22

The observations presented here suggest several productive avenues for research into the etiology of KD. The data suggest that oropharyngeal swabs from patients, particularly infants, coupled with in-home or local air sampling followed by metagenomic sequencing may be instructive. Focusing on the home environment for infants may be more productive, as their exposures are potentially more limited. The pandemic has shown that limiting exposures to aerosols and large droplets through some combination of masking, social distancing, and hand hygiene can reduce the incidence of KD in diverse communities throughout the globe.

This study has limitations. First, small sample sizes limit the strength of conclusions possible from these analyses; this is all the more so in the pandemic as case numbers were reduced. As a result, seasonal breakdowns should be considered exploratory, and mobility and pollution data associated with the pandemic period need to be interpreted with care because of even smaller-than-usual sample sizes. In addition, KD incidence shows high interannual variability (for example, compare Figure 1 B, which shows historical mean incidence and confidence intervals for San Diego, with eFigure 1 in Supplement 1 , which shows individual year incidence rates for San Diego). This makes statistical determination of anomalous incidence more difficult. Although we were able to capture a national snapshot of KD case numbers before and during the pandemic, we only studied the rebound in case numbers in the San Diego region. Similarly, we did not have access to detailed clinical or mobility data for the national data set.

Mobility data were based on mobile phone data and aggregated to the CBG level (usually a few thousand individuals). Income and pollution data were also aggregated to the CBG level. As such, the extent to which these data reflect the circumstances of individual children (ie, patients with KD) is uncertain. This may be especially the case for cell phone–derived mobility data. Our environmental data were limited to no 2 exposure, and we did not have detailed aerosol particle data, including specific species. Additionally, it is possible that some of the patients with KD were misclassified as having MIS-C (or vice versa) because of the clinical signs that overlap between the 2 conditions.

In this study of KD incidence in the United States between 2018 and 2020, the national and local (San Diego region) reduction in KD cases was associated with a period of school closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses, which all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with the lifting of the mask mandates. The results presented here are consistent with a respiratory portal of entry for the trigger(s) of KD.

Accepted for Publication: April 29, 2022.

Published: June 17, 2022. doi:10.1001/jamanetworkopen.2022.17436

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Burney JA et al. JAMA Network Open .

Corresponding Author: Jane C. Burns, MD, Department of Pediatrics, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92037 ( [email protected] ).

Author Contributions : Drs Burns and Burney had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Burney, DeHaan, Cayan, Burns.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Burney, DeHaan, Bainto, Burns.

Critical revision of the manuscript for important intellectual content: Burney, Roberts, DeHaan, Shimizu, Newburger, Dominguez, Jone, Jaggi, Szmuszkovicz, Rowley, Samuy, Scalici, Tremoulet, Cayan, Burns.

Statistical analysis: Burney, DeHaan, Cayan.

Obtained funding: Newburger, Burns.

Administrative, technical, or material support: Roberts, Shimizu, Bainto, Dominguez, Jone, Samuy, Tremoulet, Cayan.

Conflict of Interest Disclosures: Dr Dominguez reported receiving grants from Biofire Diagnostics and Pfizer and consulting for Karius, Biofire Diagnostics, and DiaSorin Molecular outside the submitted work. Dr Rowley reported receiving grants from the National Institutes of Health outside the submitted work and having a patent for Antigens and Antibodies of Kawasaki disease pending. No other disclosures were reported.

Funding/Support: This study was funded by the Gordon and Marilyn Macklin Foundation and the Patient-Centered Outcomes Research Institute.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Nonauthor Group Members: KIDCARE Study Investigators are listed in Supplement 2 .

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Medical Research Internship For Kawasaki Disease

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Job description

Are you passionate about making a real difference in saving lives? Are you looking for the opportunity to gain valuable work experience to help bolster your CV? Are you hardworking and enthusiastic? We are offering unpaid internship opportunities for recent graduates or students currently studying in Biology, Biomedical Sciences, Medicine or related disciplines for a period of 1-6 months. Interested? Well, as our intern you will be working under the guidance of Dr Qian Xu, who is an Emergency Medicine Doctor, and get a wide-range of hands on experiences that will include data analysis and research on Kawasaki Disease, day-to-day liaising and integrating with the core team to complete key priorities and a chance to help develop awareness of Kawasaki Disease and to make a real difference! You will have communication and correspondence with world renowned specialists from Imperial College and the Kawasaki Fund in Australia, and Dr. Kawasaki himself. The Kawasaki Fund internship is an excellent opportunity for ambitious graduates to contribute to developing awareness and statistical data regarding this obscure condition and the impact it has on lives. We are looking for team players and people who want to work in a vibrant energetic environment. We are looking for individuals who are highly organised, self-starters with a proactive and professional attitude and outstanding interpersonal skills. Those who complete the internship successfully and impress will gain the opportunity for a permanent, paid job. Personal requirements Very strong written and spoken English: additional language is a plus. Ability to work in the UK is required. Poised decision making skills and the capability to prioritise workload effectively Competency in Word, PowerPoint and other Office programs essential A genuine interest and passion for Charitable work Available immediately for a minimum of 3 months (ideally 6 months) Interviews will be held on a rolling basis Company information Kawasaki Fund is a charity with the mission to save lives by promoting prompt diagnosis and raising awareness of the classic symptoms of an infection that triggers the heart disease, the leading cause of paediatric heart condition. The Kawasaki Fund internship is an excellent opportunity for ambitious students to learn about charity work and to gain some valuable work experience to bolster your CV.

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- Recent graduate (no more than 1-2 years post graduate work experience) or current student at a leading school with discipline in Biology, Biomedical Sciences, Medicine or any related disciplines. - Excellent academic record and a high level of medical understanding and statistical familiarity.

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  • Kawasaki disease

Kawasaki disease causes swelling, called inflammation, in the walls of small to medium-sized blood vessels that carry blood throughout the body. Kawasaki disease most often affects the heart arteries in children. Those arteries supply oxygen-rich blood to the heart.

Kawasaki disease is sometimes called mucocutaneous lymph node syndrome. That's because it also causes swelling in glands, called lymph nodes, and mucous membranes inside the mouth, nose, eyes and throat.

Children with Kawasaki disease might have high fever, swollen hands and feet with skin peeling, and red eyes and tongue. But Kawasaki disease is often treatable. With early treatment, most children get better and have no long-lasting problems.

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Symptoms of Kawasaki disease include a fever greater than 102.2 degrees Fahrenheit (39 degrees Celsius) for five or more days. And the child has at least four of the following symptoms.

  • A rash on the main part of the body or in the genital area.
  • An enlarged lymph node in the neck.
  • Very red eyes without a thick discharge.
  • Red, dry, cracked lips and a red, swollen tongue.
  • Swollen, red skin on the palms of the hands and the soles of the feet. Later the skin on fingers and toes peels.

The symptoms might not happen at the same time. Let your child's healthcare professional know about a symptom that has gone away.

Other symptoms might include:

  • Belly pain.
  • Joint pain.

Some children get a high fever for five or more days but have fewer than four of the symptoms needed for a diagnosis of Kawasaki disease. They might have what's called incomplete Kawasaki disease. Children with incomplete Kawasaki disease are still at risk of damage to the heart arteries. They still need treatment within 10 days of when symptoms appear.

Kawasaki disease can have symptoms like those of a condition called multisystem inflammatory syndrome in children. The syndrome happens in children with COVID-19.

When to see a doctor

If your child has a fever that lasts more than three days, contact your child's healthcare professional. Treating Kawasaki disease within 10 days of when it began may reduce the chances of lasting damage to the arteries that supply the heart.

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No one knows what causes Kawasaki disease. But experts don't believe the disease spreads from person to person. Some think that Kawasaki disease happens after a bacterial or viral infection, or that it's linked to factors in the environment. Certain genes might make children more likely to get Kawasaki disease.

Risk factors

Three things are known to increase a child's risk of developing Kawasaki disease.

  • Age. Children under 5 years old are at highest risk of Kawasaki disease.
  • Sex. Children who are assigned male at birth are slightly more likely to get Kawasaki disease.
  • Ethnicity. Children of Asian or Pacific Islander descent have higher rates of Kawasaki disease.

Kawasaki disease tends to occur seasonally. In North America and countries with like climates, it most often happens in the winter and early spring.


Kawasaki disease is a leading cause of heart disease in children who live in developed countries. But, with treatment, few children have lasting damage.

Heart complications include:

  • Swelling of blood vessels, most often the arteries that send blood to the heart.
  • Swelling of the heart muscle.
  • Heart valve problems.

Any of these complications can damage the heart. Swelling of the heart arteries can weaken them and cause a bulge in the artery wall, called an aneurysm. Aneurysms raise the risk of blood clots. These can lead to a heart attack or cause bleeding inside the body.

Rarely, for children who get heart artery problems, Kawasaki disease can cause death.

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  • Ferri FF. Kawasaki disease. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed Sept. 3, 2021.
  • Elsevier Point of Care. Clinical overview: Kawasaki disease. https://www.clinicalkey.com. Accessed Aug. 10, 2023.
  • AskMayoExpert. Kawasaki disease (child). Mayo Clinic; 2023.
  • Sundel R. Kawasaki disease: Clinical features and diagnosis. https://www.uptodate.com/contents/search. Accessed Aug. 10, 2023.
  • Sundel R. Kawasaki disease: Initial treatment and prognosis. https://www.uptodate.com/contents/search. Accessed Aug. 10, 2023.
  • Rife E, et al. Kawasaki disease: An update. Current Rheumatology Reports. 2020; doi:10.1007/s11926-020-00941-4.

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Kawasaki Disease: Blocking Protein Improves Cardiac Effects, Investigators Report

Findings from research by Cedars-Sinai investigators demonstrated a link between  cardiac dysfunction and arrythmias experienced by patients with Kawasaki disease and a target for an experimental treatment for the disease. Photo by Getty.

A new study by Cedars-Sinai investigators found that blocking a protein called interleukin - 1 -beta improved cardiac dysfunction and arrythmias in Kawasaki disease , a rare illness that affects children and causes their blood vessels to swell and become inflamed.

Moshe Arditi, MD

Kawasaki disease was first described by Japanese pediatrician Tomisaku Kawasaki in 1967, but its cause remains unknown. The condition typically affects children under the age of 5, and patients with the disease usually present with a sudden, high fever; rash; redness of eyes, lips and tongue; and swelling of hands and feet that last for 10 days or longer.

In Japan, Kawasaki disease cases are on the rise after a significant decrease in 2020.

“The disease is treatable in most children if caught early, but some children continue to have fever and become at risk of developing cardiovascular complications, such as coronary artery aneurysms or arrhythmias,” said Moshe Arditi, MD , executive vice chair of the Department of Pediatrics for Research at Cedars-Sinai Guerin Children’s, the GUESS?/Fashion Industries Guild Chair in Community Child Health, and a co-senior author of the study.

The standard of care for children with Kawasaki disease is to administer intravenous immunoglobulin and aspirin to reduce inflammation and fever. But recent clinical trials have found that blocking proteins called inflammatory cytokines, such as t umor necrosis factor alpha or interleukin - 1 -beta, improves symptoms in children.

Eugenio Cingolani, MD

This study sought to identify which cytokines might be involved in the biologic processes that cause cardiovascular complications in children with Kawasaki disease.

Arditi, who is also director of the Infectious and Immunological Diseases Research Center in the Department of Biomedical Sciences and a professor of Pediatrics, and Eugenio Cingolani, MD , who is director of Cardiogenetics and Preclinical Research at the Smidt Heart Institute at Cedars-Sinai and an associate professor of Cardiology, brought their labs together to work on the study.

Together, the investigators studied publicly available datasets showing gene expressions in children with Kawasaki disease. They found elevated expression of the genes of cytokines interleukin - 1 -beta and t umor necrosis factor alpha in patients with the disease.

“We sought to identify whether one protein caused more cardiac dysfunction and arrythmias in this mouse model of Kawasaki disease,” Cingolani said.

Thassio Ricard Ribeiro Mesquita, PhD

“We need to test whether these observations in an animal disease model remain true in children with Kawasaki disease,” said Thassio Ricard Ribeiro Mesquita , PhD , a research scientist with the Smidt Heart Institute, an assistant professor of Cardiology at Cedars-Sinai and first author of the study. “If so, they would further support the use of therapies that block interleukin - 1-beta in patients with Kawasaki disease.”

Based on the experimental studies from the Arditi Laboratory on the role of interleukin-1-beta in Kawasaki disease, anakinra—the drug that blocks the interleukin-1 receptor—is now in Phase III clinical trials in children.

Other Cedars-Sinai investigators who worked on the study include Shuang Chen, Youngho Lee, Rodrigo Miguel-dos-Santos, Asli Atici, Magali Noval Rivas and Yen-Nien Lin.

The study was funded by the National Institutes of Health, the American Heart Association, the California Institute for Regenerative Medicine and the Cedars-Sinai Board of Governors.

Follow  Cedars-Sinai Academic Medicine  on X for more on the latest basic science and clinical research from Cedars-Sinai.

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Jun 30, 2023

Original Article

Case Report



Most cited articles, current issue: jun 2023, vol. 1, no. 1.


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  1. Working in the Center for Cardiovascular Research

  2. Kawasaki disease , داء كوزاكي


  1. Participate in Research

    The Kawasaki Disease Foundation is a 501 (c) (3) nonprofit organization. The Foundation's tax exemption number and federal tax ID are 17053137024021 and 04-3536123, respectively. KDF is supported by donations and volunteers. We have no paid staff, and our operating costs are minimal.

  2. Medical Research Internship for Kawasaki Disease

    The Kawasaki Fund internship is an excellent opportunity for ambitious students to learn about charity work and to gain some valuable work experience to bolster your CV. Desired profile - Recent graduate (no more than 1-2 years post graduate work experience) or current student at a leading school with discipline in Biology, Biomedical Sciences ...

  3. UC San Diego Kawasaki Disease Research Center

    The Kawasaki Disease Research Center is a joint collaboration between the Departments of Pediatrics, Medicine, and Family and Preventive Medicine and Sociology at UCSD, the Scripps Institute of Oceanography, and Rady Children's Hospital San Diego. The Program was created to help foster excellence in care for patients with Kawasaki Disease (KD ...

  4. Kawasaki Disease Research

    Kawasaki Disease Research. Lurie Children's has been a leader in clinical research on Kawasaki disease dating back to the treatment trials in the 1980s and early 1990s. Our clinician scientists are continuing their research efforts in finding the cause of this illness, improving treatment and identifying factors that determine susceptibility.

  5. Current Research Studies

    Active Clinical Trials. Current Kawasaki Disease Research Studies. Adult KD Collaborative. This collaboration with colleagues in adult cardiology seeks to answer important questions about the long term outcome for adults who suffered from KD in childhood. Young adults who have had KD in childhood should contact our study coordinator at adultkd ...

  6. Research Team

    She was Chief of the Division of Allergy, Immunology, and Rheumatology from 2000 to 2013. Currently, Dr. Burns is Director of the Kawasaki Disease Research Center at UCSD/Rady Children's Hospital where she leads a multidisciplinary team that cares for 90-100 new Kawasaki Disease patients each year and follows over 1,300 families in the KD Clinic.

  7. Kawasaki Disease's Post

    KAWASAKI FUND CHARITY REG:1064518. Interns invited! Exciting opportunity for a bright medical research student to intern with us at Kawasaki Disease UK. Our office is in West London. If you are ...

  8. Kawasaki disease: pathophysiology and insights from mouse models

    Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term ...

  9. Clinical Research Internship Program

    The Clinical Research Internship program with the University of Louisville Division of Infectious Diseases hosts two cohorts each year with 20-30 participants per cohort. Applications from qualified candidates are accepted twice per year. To be considered, applicants must submit all required materials during the open application process.

  10. 2021 Update on the Clinical Management and Diagnosis of Kawasaki Disease

    The efficacy of other agents (atorvastatin, doxycycline) is currently being investigated. MIS-C is a clinically distinct entity from KD with broad clinical manifestations and multiorgan involvement (cardiac, GI, hematologic, dermatologic, respiratory, renal). MIS-C with Kawasaki manifestations is more commonly seen in children < 5 years of age.

  11. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A

    Pathology of Kawasaki disease: I: pathology and morphogenesis of the vascular changes. Jpn Circ J. 1979; 43:633-643. Crossref Medline Google Scholar; 75. Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki disease: with particular emphasis on arterial lesions. Acta Pathol Jpn. 1991; 41:785-797. Medline Google Scholar; 76. Landing BH, Larson EJ.

  12. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A

    Epidemiology. In the past, the illness may have masqueraded in various guises, and old reports on infantile polyarteritis nodosa in Western countries describe pathological findings identical to those of fatal KD. 4-8 First described in Japan, KD has now been described worldwide. 9-17 However, the disease is markedly more prevalent in children in Japan, where the annual incidence was 243.1 ...

  13. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease

    With careful clinical follow-up 10 to 20 years after the onset of Kawasaki disease, patients with no coronary artery changes on echocardiography at any stage of the illness seem to demonstrate a risk for clinical cardiac events that is similar to that in the population without Kawasaki disease, 2 but research studies suggest subclinical ...

  14. Diagnosis, Progress, and Treatment Update of Kawasaki Disease

    Kawasaki disease (KD) is an acute inflammatory disorder that primarily affects children and can lead to coronary artery lesions (CAL) if not diagnosed and treated promptly. The original clinical criteria for diagnosing KD were reported by Dr. Tomisaku Kawasaki in 1967 and have been used for decades.

  15. Epidemiological and Clinical Features of Kawasaki Disease During the

    In the United States, a multicenter clinical trial for KD (Kawasaki Disease Comparative Effectiveness ... Data from the KD Research Center at Rady Children's Hospital San Diego (RCHSD)/UCSD in San Diego included 1461 patients meeting the strict AHA case definition for complete and incomplete KD, with the exception of 46 individuals (3.3% ...

  16. Kawasaki Disease

    Owners: Shaila Siraj, MD; Meghan Martin, MD;; Juan Dumois, MD; Ashish Shah, MD; Courtney Titus, PA-C Updated July 2021

  17. Kawasaki disease

    Treatment for Kawasaki disease can include: Gamma globulin. A protein called gamma globulin is given through a vein. This treatment lowers inflammation in the blood vessels. It can lower the risk of problems with the heart artery. With treatment, a child might start to improve soon after one gamma globulin treatment.

  18. Medical Research Internship For Kawasaki Disease

    The Kawasaki Fund internship is an excellent opportunity for ambitious students to learn about charity work and to gain some valuable work experience to bolster your CV. Desired profile - Recent graduate (no more than 1-2 years post graduate work experience) or current student at a leading school with discipline in Biology, Biomedical Sciences ...

  19. Kawasaki disease

    Symptoms of Kawasaki disease include a fever greater than 102.2 degrees Fahrenheit (39 degrees Celsius) for five or more days. And the child has at least four of the following symptoms. A rash on the main part of the body or in the genital area. An enlarged lymph node in the neck. Very red eyes without a thick discharge.

  20. Kawasaki Disease: Blocking Protein Improves Cardiac Effects

    The standard of care for children with Kawasaki disease is to administer intravenous immunoglobulin and aspirin to reduce inflammation and fever. But recent clinical trials have found that blocking proteins called inflammatory cytokines, such as t umor necrosis factor alpha or interleukin-1-beta, improves symptoms in children.

  21. Kawasaki Disease

    Kawasaki disease is a vasculitis that presents with fever and affects medium-sized arteries throughout the body. Although the etiology and pathophysiology of Kawasaki disease remain unknown, the emergence of the multisystem inflammatory syndrome in children (MIS-C) in 2020 is of significant interest due to its similarity in symptoms of Kawasaki disease and its association with SARS-CoV-2.

  22. Medical Research Internship For Kawasaki Disease

    The Kawasaki Fund internship is an excellent opportunity for ambitious students to learn about charity work and to gain some valuable work experience to bolster your CV. Qualifications - Recent graduate (no more than 1-2 years post graduate work experience) or current student at a leading school with discipline in Biology, Biomedical Sciences ...